Methods for treating HCV

ABSTRACT

The present invention features interferon-free therapies for the treatment of HCV. Preferably, the treatment is over a shorter duration, such as no more than 12 weeks. In one aspect, the therapies comprise administering at least two direct acting antiviral agents and ribavirin to a subject with HCV infection. For example, the therapies comprise administering to the subject effective amounts of therapeutic agent 1, therapeutic agent 2 (or therapeutic agent 3), an inhibitor of cytochrome P450 (e.g., ritonavir), and ribavirin.

This application is a continuation of U.S. patent application Ser. No.13/935,983, filed Jul. 5, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/912,601 filed Jun. 7, 2013, now abandoned, whichis a continuation of U.S. patent application Ser. No. 13/603,022 filedSep. 4, 2012, now U.S. Pat. No. 8,466,159, which claims the benefit ofU.S. Provisional Application No. 61/550,352 filed Oct. 21, 2011, U.S.Provisional Application No. 61/562,181 filed Nov. 21, 2011, U.S.Provisional Application No. 61/587,225 filed Jan. 17, 2012, U.S.Provisional Application No. 61/600,276 filed Feb. 17, 2012, U.S.Provisional Application No. 61/619,870 filed Apr. 3, 2012, and U.S.Provisional Application No. 61/656,251 filed Jun. 6, 2012.

FIELD OF THE INVENTION

The present invention relates to interferon-free treatment for hepatitisC virus (HCV).

BACKGROUND OF THE INVENTION

The HCV is an RNA virus belonging to the Hepacivirus genus in theFlaviviridae family. The enveloped HCV virion contains a positivestranded RNA genome encoding all known virus-specific proteins in asingle, uninterrupted, open reading frame. The open reading framecomprises approximately 9500 nucleotides and encodes a single largepolyprotein of about 3000 amino acids. The polyprotein comprises a coreprotein, envelope proteins E1 and E2, a membrane bound protein p7, andthe non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

Chronic HCV infection is associated with progressive liver pathology,including cirrhosis and hepatocellular carcinoma. Chronic hepatitis Cmay be treated with peginterferon-alpha in combination with ribavirin.Substantial limitations to efficacy and tolerability remain as manyusers suffer from side effects, and viral elimination from the body isoften incomplete. Therefore, there is a need for new therapies to treatHCV infection.

BRIEF SUMMARY OF THE INVENTION

As one aspect of the present invention, methods for treating HCVinfection in a subject are provided. The methods comprise administeringat least two direct acting antiviral agents (DAAs) and ribavirin for aduration of no more than twelve weeks, or for another duration as setforth herein. Preferably, the duration of the treatment is twelve weeks.The duration of the treatment can also be no more than eight weeks.Preferably, the two or more direct acting antiviral agents (DAAs) andribavirin are administered in amounts effective to provide a sustainedvirological response (SVR) or achieve another desired measure ofeffectiveness in a subject. The subject is not administered interferonduring the treatment regimen. Put another way, the methods exclude theadministration of interferon to the subject, thereby avoiding the sideeffects associated with interferon. In some embodiments, the methodsfurther comprise administering an inhibitor of cytochrome P-450 (such asritonavir) to the subject to improve the pharmacokinetics orbioavailability of one or more of the DAAs.

As another aspect, methods for treating HCV infection in a subject areprovided. The methods comprise administering (a) therapeutic agent 1,(b) at least one polymerase inhibitor selected from the group consistingof therapeutic agent 2, therapeutic agent 3, and combinations thereof,(c) ribavirin and (d) an inhibitor of cytochrome P-450 to the subjectfor a duration of no more than twelve weeks, or for another duration asset forth herein (e.g., the treatment regimen can last a duration of forno more than 8 weeks). Preferably, therapeutic agent 1, the polymeraseinhibitor(s), ribavirin and the inhibitor of cytochrome P-450 areadministered in amounts effective to provide high rates of SVR oranother measure of effectiveness in the subject. As non-limitingexamples, therapeutic agent 1 and the inhibitor of cytochrome P-450 canbe co-formulated and administered once daily, and the polymeraseinhibitor(s) can be administered once daily or twice daily, and thetreatment regimen preferably lasts for twelve weeks (the treatmentregimen can also last, for example, for eight weeks).

As still another aspect, methods for treating a population of subjectshaving HCV infection are provided. The methods comprise administering atleast two DAAs, together with ribavirin, to the subjects for a durationof no more than 12 weeks. Preferably, the at least two DAAs areadministered to the subjects in amounts effective to result in SVR oranother measure of effectiveness in at least about 50% of thepopulation, preferably at least about 70% of the population.

In the foregoing methods as well as methods described hereinbelow, theDAAs can be selected from the group consisting of protease inhibitors,nucleoside or nucleotide polymerase inhibitors, non-nucleosidepolymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NS5Ainhibitors, NS5B inhibitors, cyclophilin inhibitors, and combinations ofany of the foregoing. For example, in some embodiments, the DAAs used inthe present methods comprise or consist of at least one HCV proteaseinhibitor and at least one HCV polymerase inhibitor. The HCV polymeraseinhibitor can be a nucleotide or nucleoside polymerase inhibitor or anon-nucleoside polymerase inhibitor. The HCV polymerase inhibitor canalso be a non-nucleotide polymerase inhibitor.

In some embodiments, the HCV protease inhibitor is therapeutic agent 1(described below) and the HCV polymerase inhibitor is therapeutic agent2 and/or therapeutic agent 3 (also described below). By way of example,therapeutic agent 1 can be administered a total daily dose of from about100 mg to about 250 mg, or administered at least once daily at a dose offrom about 150 mg to about 250 mg, and therapeutic agent 2 isadministered in a total daily dose of from about 300 mg to about 1800 mgor administered at least twice daily at doses from about 200 mg to about400 mg. For some embodiments, the HCV protease inhibitor is therapeuticagent 1 and the non-nucleoside HCV polymerase inhibitor is therapeuticagent 3. By way of example, therapeutic agent 1 can be administered at atotal daily dose of about 100 mg, alternatively about 200 mg, oralternatively about 250 mg; and therapeutic agent 3 is administered at atotal daily dose of about 400 mg. Ritonavir (or another cytochrome P-4503A4 inhibitor) can be co-administered with therapeutic agent 1 toimprove the pharmacokinetics and bioavailability of therapeutic agent 1.

In some embodiments, the at least two DAAs comprise at least one HCVprotease inhibitor and at least one NS5A inhibitor. Preferably, the HCVprotease inhibitor is therapeutic agent 1 and the NS5A inhibitor istherapeutic agent 4. By way of example, therapeutic agent 1 can beadministered at a total daily dosage from about 100 mg to about 250 mg,and therapeutic agent 4 can be administered in a total daily dose fromabout 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4inhibitor) can be co-administered with therapeutic agent 1 to improvethe pharmacokinetics and bioavailability of therapeutic agent 1.

In the foregoing methods as well as methods described herein, the DAAsand ribavirin can be administered in any effective dosing schemes and/orfrequencies, for example, they can each be administered daily. Each DAAcan be administered either separately or in combination, and each DAAcan be administered at least once a day, at least twice a day, or atleast three times a day. Likewise, the ribavirin can be administered atleast once a day, at least twice a day, or at least three times a day,either separately or in combination with one or more of the DAAs. Insome preferred embodiments, therapeutic agent 3 is administered oncedaily (QD) or twice daily (BID), and therapeutic agent 1 is administeredonce daily.

In some aspects, the present technology provides a method for treatingHCV infection comprising administering to a subject in need thereof atleast two DAAs and ribavirin for a duration of no more than twelveweeks, wherein the subject is not administered with interferon duringsaid duration. In some aspects, the at least two DAAs and ribavirin areadministered in an amount effective to result in SVR. Some methodsfurther comprise administering an inhibitor of cytochrome P450 to thesubject. In some aspects, the duration is no more than eight weeks.

In some aspects of the present technology, the at least two directacting antiviral agents comprise (i) Compound 1 or a pharmaceuticallyacceptable salt thereof, which is co-administered or co-formulated withritonavir, and (ii) Compound 2 or a pharmaceutically acceptable saltthereof.

In other aspects, the at least two direct acting antiviral agentscomprise (i) Compound 1 or a pharmaceutically acceptable salt thereof,which is co-administered or co-formulated with ritonavir, and (ii)Compound 3 or a pharmaceutically acceptable salt thereof.

In yet another aspect, the at least two direct acting antiviral agentscomprise (i) Compound 1 or a pharmaceutically acceptable salt thereof,which is co-administered or co-formulated with ritonavir, and (ii)compound 4 or a pharmaceutically acceptable salt thereof.

In yet a further aspect, the at least two direct acting antiviral agentscomprise (i) Compound 1 or a pharmaceutically acceptable salt thereof,which is co-administered or co-formulated with ritonavir, (ii) Compound2 or a pharmaceutically acceptable salt thereof, and (iii) compound 4 ora pharmaceutically acceptable salt thereof.

In yet another aspect, the at least two direct acting antiviral agentscomprises a drug combination selected from the group consisting of: acombination of PSI-7977 and PSI-938, a combination of BMS-790052 andBMS-650032, a combination of GS-5885 and GS-9451, a combination ofGS-5885, GS-9190 and GS-9451, a combination of BI-201335 and BI-27127, acombination of telaprevir and VX-222, a combination of PSI-7977 andTMC-435, and a combination of danoprevir and R7128. In yet anotheraspect, the at least two direct acting antiviral agents comprises acombination of PSI-7977 and BMS-790052 (daclatasvir). In yet anotheraspect, the at least two direct acting antiviral agents comprises acombination of PSI-7977 and BMS-650032 (asunaprevir). In still anotheraspect, the at least two direct acting antiviral agents comprises acombination of PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir).

In other aspects, the present technology provides a method for treatingHCV infection in a subject comprising administering (a) therapeuticagent 1, (b) at least one polymerase inhibitor selected from the groupconsisting of therapeutic agent 2, therapeutic agent 3 and combinationsthereof, (c) ribavirin and (d) an inhibitor of cytochrome P450 to thesubject and for a duration of no more than twelve weeks, wherein thetherapeutic agent 1, the at least one polymerase inhibitor, theribavirin and the inhibitor of cytochrome P450 are administered inamounts effective to result in sustained virological response (SVR) inthe subject.

In yet another aspect, the present technology provides a method fortreating a population of subjects having HCV infection, the methodcomprising administering at least two DAAs to the subjects for aduration of no more than 12 weeks, wherein the at least two DAAs areadministered to the subjects in amounts and for a duration effective toprovide a SVR in at least about 70% of the population.

In another aspect, the present technology features a combination of atleast two DAAs for use in treating HCV infection, wherein the durationof the treatment regimen is no more than twelve weeks (e.g., theduration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4,or 3 weeks). The treatment comprises administering the at least two DAAsto a subject infected with HCV. Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon. The treatment may also include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The at least two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and another DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder, a partial responder or a relapser), or not a candidatefor interferon treatment.

In another aspect, the present technology features a combination ofCompound 1 (or a pharmaceutically acceptable salt thereof) and Compound2 (or a pharmaceutically acceptable salt thereof) for use in treatingHCV infection. The treatment comprises administering the DAAs to asubject infected with HCV. The duration of the treatment regimen is nomore than twelve weeks (e.g., the duration being 12 weeks; or theduration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, theduration of the treatment regimen is twelve weeks. The duration of thetreatment can also last, for example, no more than eight weeks (e.g.,the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3weeks). The treatment includes administering ribavirin but does notinclude administering interferon; and ritonavir or another CYP3A4inhibitor (e.g., cobicistat) is administered with Compound 1 (or thesalt thereof) to improve the pharmacokinetics of the latter. Compound 1(or the salt thereof) and Compound 2 (or the salt thereof) can beadministered concurrently or sequentially. For example, Compound 1 (orthe salt thereof) can be administered once daily, together withritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and Compound 2(or the salt thereof) can be administered twice daily. For yet anotherexample, Compound 1 (or the salt thereof) and ritonavir (or anotherCYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). For yetanother example, Compound 1 (or the salt thereof), co-formulated withritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), isadministered once daily, and Compound 2 (or the salt thereof) isadministered twice daily. As a non-limiting example, the patient beingtreated can be infected with HCV genotype 1, such as genotype 1a or 1b.As another non-limiting example, the patient can be infected with HCVgenotype 2 or 3. As yet another non-limiting example, the patient can bea HCV-treatment naïve patient, a HCV-treatment experienced patient, aninterferon non-responder (e.g., a null responder), or not a candidatefor interferon treatment. In one example, the treatment lasts for 12weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In another example, the treatment lasts for 11 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 9 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In another example, the treatment lasts for 11 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In still another example, the treatment lasts for 10 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In yetanother example, the treatment lasts for 8 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 11 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 8 weeks, and the subjectbeing treated is a non-responder infected (e.g., a null responder) withHCV genotype 1.

In another aspect, the present technology features a combination ofCompound 1 (or a pharmaceutically acceptable salt thereof) and Compound3 (or a pharmaceutically acceptable salt thereof) for use in treatingHCV infection. The treatment comprises administering the DAAs to asubject infected with HCV. The duration of the treatment regimen is nomore than twelve weeks (e.g., the duration being 12 weeks; or theduration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, theduration of the treatment regimen is twelve weeks. The duration of thetreatment can also last, for example, no more than eight weeks (e.g.,the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3weeks). The treatment includes administering ribavirin but does notinclude administering interferon; and ritonavir or another CYP3A4inhibitor (e.g., cobicistat) is administered with Compound 1 (or thesalt thereof) to improve the pharmacokinetics of the latter. Compound 1(or the salt thereof) and Compound 3 (or the salt thereof) can beadministered concurrently or sequentially. For example, Compound 1 (orthe salt thereof) can be administered once daily, together withritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and Compound 3(or the salt thereof) can be administered twice daily. For anotherexample, Compound 1 (or the salt thereof) and Compound 3 (or the saltthereof) are administered once daily. For yet another example, Compound1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor,e.g., cobicistat) are co-formulated in a single composition andadministered concurrently (e.g., once daily). For yet another example,Compound 1 (or the salt thereof), ritonavir (or another CYP3A4inhibitor, e.g., cobicistat), and Compound 3 (or the salt thereof) areco-formulated in a single composition and administered concurrently(e.g., once daily). As a non-limiting example, the patient being treatedcan be infected with HCV genotype 1, such as genotype 1a or 1b. Asanother non-limiting example, the patient can be infected with HCVgenotype 2 or 3. As yet another non-limiting example, the patient can bea HCV-treatment naïve patient, a HCV-treatment experienced patient, aninterferon non-responder (e.g., a null responder), or not a candidatefor interferon treatment. In one example, the treatment lasts for 12weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In another example, the treatment lasts for 11 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 9 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In another example, the treatment lasts for 11 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In still another example, the treatment lasts for 10 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In yetanother example, the treatment lasts for 8 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 11 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 8 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In another aspect, the present technology features a combination ofCompound 1 (or a pharmaceutically acceptable salt thereof) and compound4 (or a pharmaceutically acceptable salt thereof) for use in treatingHCV infection. The treatment comprises administering the DAAs to asubject infected with HCV. The duration of the treatment regimen is nomore than twelve weeks (e.g., the duration being 12 weeks; or theduration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, theduration of the treatment regimen is twelve weeks. The duration of thetreatment can also last, for example, no more than eight weeks (e.g.,the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3weeks). The treatment includes administering ribavirin but does notinclude administering interferon; and ritonavir or another CYP3A4inhibitor (e.g., cobicistat) is administered with Compound 1 (or thesalt thereof) to improve the pharmacokinetics of the latter. Compound 1(or the salt thereof) and compound 4 (or the salt thereof) can beadministered concurrently or sequentially. For example, Compound 1 (orthe salt thereof) can be administered once daily, together withritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and compound 4(or the salt thereof) can be administered twice daily. For anotherexample, Compound 1 (or the salt thereof) and compound 4 (or the saltthereof) are administered once daily. For yet another example, Compound1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor,e.g., cobicistat) are co-formulated in a single composition andadministered concurrently (e.g., once daily). For yet another example,Compound 1 (or the salt thereof), ritonavir (or another CYP3A4inhibitor, e.g., cobicistat), and compound 4 (or the salt thereof) areco-formulated in a single composition and administered concurrently(e.g., once daily). As a non-limiting example, the patient being treatedcan be infected with HCV genotype 1, such as genotype 1a or 1b. Asanother non-limiting example, the patient can be infected with HCVgenotype 2 or 3. As yet another non-limiting example, the patient can bea HCV-treatment naïve patient, a HCV-treatment experienced patient, aninterferon non-responder (e.g., a null responder), or not a candidatefor interferon treatment. In one example, the treatment lasts for 12weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In another example, the treatment lasts for 11 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 9 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In another example, the treatment lasts for 11 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In still another example, the treatment lasts for 10 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In yetanother example, the treatment lasts for 8 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 11 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 8 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In another aspect, the present technology features a combination ofCompound 1 (or a pharmaceutically acceptable salt thereof), Compound 2(or a pharmaceutically acceptable salt thereof), and compound 4 (or apharmaceutically acceptable salt thereof) for use in treating HCVinfection. The treatment comprises administering the DAAs to a subjectinfected with HCV. The duration of the treatment regimen is no more thantwelve weeks (e.g., the duration being 12 weeks; or the duration being11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon; and ritonavir or another CYP3A4 inhibitor(e.g., cobicistat) is administered with Compound 1 (or the salt thereof)to improve the pharmacokinetics of the latter. Compound 1 (or the saltthereof), Compound 2 (or the salt thereof), and compound 4 (or the saltthereof) can be administered concurrently or sequentially. For example,Compound 1 (or the salt thereof) can be administered once daily,together with ritonavir or another CYP3A4 inhibitor (e.g., cobicistat),and compound 4 (or the salt thereof) can be administered once daily, andCompound 2 (or the salt thereof) can be administered twice daily. Foryet another example, Compound 1 (or the salt thereof), compound 4 (orthe salt thereof), and ritonavir (or another CYP3A4 inhibitor, e.g.,cobicistat) are co-formulated in a single composition and administeredconcurrently (e.g., once daily). For yet another example, Compound 1 (orthe salt thereof), ritonavir (or another CYP3A4 inhibitor, e.g.,cobicistat), and compound 4 (or the salt thereof) are co-formulated in asingle composition and administered concurrently (e.g., once daily), andCompound 2 (or the salt thereof) are administered twice daily. As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment. In oneexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 1. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 2. In another example, the treatmentlasts for 11 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In still another example, the treatmentlasts for 10 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 9 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 8 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 12 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In another example, the treatment lastsfor 11 weeks, and the subject being treated is a naïve patient infectedwith HCV genotype 3. In still another example, the treatment lasts for10 weeks, and the subject being treated is a naïve patient infected withHCV genotype 3. In yet another example, the treatment lasts for 9 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 3. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCV genotype3. In yet another example, the treatment lasts for 12 weeks, and thesubject being treated is a non-responder (e.g., a null responder)infected with HCV genotype 1. In another example, the treatment lastsfor 11 weeks, and the subject being treated is a non-responder (e.g., anull responder) infected with HCV genotype 1. In still another example,the treatment lasts for 10 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1. In yet another example, the treatment lasts for 8 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1.

In another aspect, the present technology features a combination of atleast two DAAs for use in treating HCV infection, wherein saidcombination comprises a combination selected from:

a combination of PSI-7977 and PSI-938,

a combination of BMS-790052 and BMS-650032,

a combination of GS-5885 and GS-9451,

a combination of GS-5885, GS-9190 and GS-9451,

a combination of BI-201335 and BI-27127,

a combination of telaprevir and VX-222,

a combination of PSI-7977 and TMC-435, and

a combination of danoprevir and R7128.

The treatment comprises administering the DAA combination to a subjectinfected with HCV. The duration of the treatment regimen is no more thantwelve weeks (e.g., the duration being 12 weeks; or the duration being11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon. The treatment may also include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The at least two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and another DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment.

In yet another aspect, the present technology features a combination ofat least two DAAs for use in treating HCV infection, wherein saidcombination comprises a combination selected from:

a combination of PSI-7977 and BMS-790052

a combination of PSI-7977 and BMS-650032,

a combination of PSI-7977, BMS-790052 and BMS-650032,

a combination of INX-189 and BMS-790052

a combination of INX-189 and BMS-650032, or

a combination of INX-189, BMS-790052 and BMS-650032.

The treatment comprises administering the DAA combination to a subjectinfected with HCV. The duration of the treatment regimen is no more thantwelve weeks (e.g., the duration being 12 weeks; or the duration being11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon. The treatment may include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The at least two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and another DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment.

In still another aspect, the present technology features PSI-7977, or acombination of at least two DAAs, for use in treating HCV infection,wherein said combination comprises a combination selected from:

a combination of mericitabine and danoprevir,

a combination of INX-189, daclatasvir and BMS-791325, and

a combination of PSI-7977 and GS-5885.

The treatment comprises administering PSI-7977 or the DAA combination toa subject infected with HCV. The duration of the treatment regimen is nomore than twelve weeks (e.g., the duration being 12 weeks; or theduration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). For example, theduration of the treatment regimen is no more than eight weeks (e.g., theduration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks).The treatment includes administering ribavirin but does not includeadministering interferon. The treatment may include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The at least two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and another DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment.

In still another aspect, the present technology features PSI-7977, or acombination of at least two DAAs, for use in treating HCV infection,wherein said combination comprises a combination selected from:

a combination of mericitabine and danoprevir,

a combination of INX-189, daclatasvir and BMS-791325, and

a combination of PSI-7977 and GS-5885.

The treatment comprises administering PSI-7977 or the DAA combination toa subject infected with HCV. The duration of the treatment regimen is nomore than twelve weeks (e.g., the duration being 12 weeks; or theduration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, theduration of the treatment regimen is twelve weeks. The duration of thetreatment can also last, for example, no more than eight weeks (e.g.,the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3weeks). The treatment includes administering ribavirin but does notinclude administering interferon. The treatment may includeadministering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat)if one of the DAAs requires pharmacokinetic enhancement. The at leasttwo DAAs can be administered concurrently or sequentially. For example,one DAA can be administered once daily, and another DAA can beadministered twice daily. For another example, the two DAAs areadministered once daily. For yet another example, the two DAAs areco-formulated in a single composition and administered concurrently(e.g., once daily). As a non-limiting example, the patient being treatedcan be infected with HCV genotype 1, such as genotype 1a or 1b. Asanother non-limiting example, the patient can be infected with HCVgenotype 2 or 3. As yet another non-limiting example, the patient can bea HCV-treatment naïve patient, a HCV-treatment experienced patient, aninterferon non-responder (e.g., a null responder), or not a candidatefor interferon treatment.

In still another aspect, the present technology features a combinationof at least two DAAs, for use in treating HCV infection, wherein saidcombination comprises a combination selected from:

a combination of tegobuvir and GS-9256,

a combination of BMS-791325, asunaprevir and daclatasvir, and

a combination of TMC-435 and daclatasvir.

The treatment comprises administering the DAA combination to a subjectinfected with HCV. The duration of the treatment regimen is no more thantwelve weeks (e.g., the duration being 12 weeks; or the duration being11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon. The treatment may include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The at least two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and another DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment.

In yet another aspect, the present technology features a combination ofPSI-7977 and BMS-790052 for use in treating HCV infection. The treatmentcomprises administering the DAA combination to a subject infected withHCV. The duration of the treatment can last, for example, no more thantwelve weeks (e.g., the duration being 12 weeks; or the duration being11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of thetreatment regimen is twelve weeks. The duration of the treatment canalso last, for example, no more than eight weeks (e.g., the durationbeing 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). Thetreatment includes administering ribavirin but does not includeadministering interferon. The treatment may include administeringritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of theDAAs requires pharmacokinetic enhancement. The two DAAs can beadministered concurrently or sequentially. For example, one DAA can beadministered once daily, and the other DAA can be administered twicedaily. For another example, the two DAAs are administered once daily.For yet another example, the two DAAs are co-formulated in a singlecomposition and administered concurrently (e.g., once daily). As anon-limiting example, the patient being treated can be infected with HCVgenotype 1, such as genotype 1a or 1b. As another non-limiting example,the patient can be infected with HCV genotype 2 or 3. As yet anothernon-limiting example, the patient can be a HCV-treatment naïve patient,a HCV-treatment experienced patient, an interferon non-responder (e.g.,a null responder), or not a candidate for interferon treatment. In oneexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 1. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 8 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 1. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 2. In another example, the treatmentlasts for 11 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In still another example, the treatmentlasts for 10 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 9 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 8 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 2. In yet another example, the treatmentlasts for 12 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In another example, the treatment lastsfor 11 weeks, and the subject being treated is a naïve patient infectedwith HCV genotype 3. In still another example, the treatment lasts for10 weeks, and the subject being treated is a naïve patient infected withHCV genotype 3. In yet another example, the treatment lasts for 9 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 3. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCV genotype3. In yet another example, the treatment lasts for 12 weeks, and thesubject being treated is a non-responder (e.g., a null responder)infected with HCV genotype 1. In another example, the treatment lastsfor 11 weeks, and the subject being treated is a non-responder (e.g., anull responder) infected with HCV genotype 1. In still another example,the treatment lasts for 10 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1. In yet another example, the treatment lasts for 8 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination ofPSI-7977 and TMC-435 for use in treating HCV infection. The treatmentcomprises administering the DAA combination to a subject infected withHCV. The duration of the treatment regimen is no more than twelve weeks(e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8,7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatmentregimen is twelve weeks. The duration of the treatment can also last,for example, no more than eight weeks (e.g., the duration being 8 weeks;or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includesadministering ribavirin but does not include administering interferon.The treatment may include administering ritonavir or another CYP3A4inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokineticenhancement. The two DAAs can be administered concurrently orsequentially. For example, one DAA can be administered once daily, andthe other DAA can be administered twice daily. For another example, thetwo DAAs are administered once daily. For yet another example, the twoDAAs are co-formulated in a single composition and administeredconcurrently (e.g., once daily). As a non-limiting example, the patientbeing treated can be infected with HCV genotype 1, such as genotype 1aor 1b. As another non-limiting example, the patient can be infected withHCV genotype 2 or 3. As yet another non-limiting example, the patientcan be a HCV-treatment naïve patient, a HCV-treatment experiencedpatient, an interferon non-responder (e.g., a null responder), or not acandidate for interferon treatment. In one example, the treatment lastsfor 12 weeks, and the subject being treated is a naïve patient infectedwith HCV genotype 1. In another example, the treatment lasts for 11weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In still another example, the treatment lasts for 10weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In yet another example, the treatment lasts for 9 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 8 weeks, andthe subject being treated is a naïve patient infected with HCV genotype1.

In yet another example, the treatment lasts for 12 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In another example, the treatment lasts for 11 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In stillanother example, the treatment lasts for 10 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 9 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 2. In yet another example,the treatment lasts for 8 weeks, and the subject being treated is anaïve patient infected with HCV genotype 2. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In another example, the treatmentlasts for 11 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In still another example, the treatmentlasts for 10 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In yet another example, the treatmentlasts for 9 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In yet another example, the treatmentlasts for 8 weeks, and the subject being treated is a naïve patientinfected with HCV genotype 3. In yet another example, the treatmentlasts for 12 weeks, and the subject being treated is a non-responder(e.g., a null responder) infected with HCV genotype 1. In anotherexample, the treatment lasts for 11 weeks, and the subject being treatedis a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 9 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 8 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In yet another aspect, the present technology features a combination ofdanoprevir and mercitabine for use in treating HCV infection. Thetreatment comprises administering the DAA combination to a subjectinfected with HCV. The duration of the treatment regimen is no more thansixteen weeks (e.g., the duration being 16 weeks; or the duration being14, 12 or 10 weeks). The duration of the treatment regimen may also beless than 10 weeks. The treatment includes administering ribavirin butdoes not include administering interferon. The treatment also includesco-administering ritonavir or another CYP3A4 inhibitor (e.g.,cobicistat) with danoprevir to improve the pharmacokinetics ofdanoprevir. The two DAAs can be administered concurrently orsequentially. For example, one DAA can be administered once daily, andthe other DAA can be administered twice daily. For another example, thetwo DAAs are administered once daily. For yet another example, the twoDAAs are co-formulated in a single composition and administeredconcurrently (e.g., once daily). As a non-limiting example, the patientbeing treated can be infected with HCV genotype 1, such as genotype 1aor 1b. As another non-limiting example, the patient can be infected withHCV genotype 2 or 3. As yet another non-limiting example, the patientcan be a HCV-treatment naïve patient, a HCV-treatment experiencedpatient, an interferon non-responder (e.g., a null responder), or not acandidate for interferon treatment. In one example, the treatment lastsfor 16 weeks, and the subject being treated is a naïve patient infectedwith HCV genotype 1. In another example, the treatment lasts for 15weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In still another example, the treatment lasts for 14weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In yet another example, the treatment lasts for 13weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In yet another example, the treatment lasts for 12weeks, and the subject being treated is a naïve patient infected withHCV genotype 1. In yet another example, the treatment lasts for 12weeks, and the subject being treated is a naïve patient infected withHCV genotype 2. In another example, the treatment lasts for 11 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In still another example, the treatment lasts for 10 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In yet another example, the treatment lasts for 9 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In yet another example, the treatment lasts for 8 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 16 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 3.In another example, the treatment lasts for 15 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 3. In stillanother example, the treatment lasts for 14 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 3. In yet anotherexample, the treatment lasts for 13 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In yet another example,the treatment lasts for 12 weeks, and the subject being treated is anaïve patient infected with HCV genotype 3. In yet another example, thetreatment lasts for 16 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 15 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 14 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 13 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 12 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In yet another aspect, the present technology features a combination ofINX-189, daclatasvir and BMS-791325 for use in treating HCV infection.The treatment comprises administering the DAA combination to a subjectinfected with HCV. The duration of the treatment regimen is no more thansixteen weeks (e.g., the duration being 16 weeks; or the duration being14, 12 or 10 weeks). The duration of the treatment regimen may also beless than 10 weeks. The treatment includes administering ribavirin butdoes not include administering interferon. The treatment may includeadministering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat)if one of the DAAs requires pharmacokinetic enhancement. The two DAAscan be administered concurrently or sequentially. For example, one DAAcan be administered once daily, and the other DAA can be administeredtwice daily. For another example, the two DAAs are administered oncedaily. For yet another example, the two DAAs are co-formulated in asingle composition and administered concurrently (e.g., once daily). Asa non-limiting example, the patient being treated can be infected withHCV genotype 1, such as genotype 1a or 1b. As another non-limitingexample, the patient can be infected with HCV genotype 2 or 3. As yetanother non-limiting example, the patient can be a HCV-treatment naïvepatient, a HCV-treatment experienced patient, an interferonnon-responder (e.g., a null responder), or not a candidate forinterferon treatment. In one example, the treatment lasts for 16 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In another example, the treatment lasts for 15 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In still another example, the treatment lasts for 14 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 13 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In another example, the treatment lasts for 11 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In still another example, the treatment lasts for 10 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In yetanother example, the treatment lasts for 8 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 16 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In another example, thetreatment lasts for 15 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In still another example, thetreatment lasts for 14 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 13 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 16 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 15 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 14 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 13 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 12 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In yet another aspect, the present technology features a combination ofPSI-7977 and GS-5885 for use in treating HCV infection. The treatmentcomprises administering the DAA combination to a subject infected withHCV. The duration of the treatment regimen is no more than sixteen weeks(e.g., the duration being 16 weeks; or the duration being 14, 12 or 10weeks). The duration of the treatment regimen may also be less than 10weeks. The treatment includes administering ribavirin but does notinclude administering interferon. The treatment may includeadministering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat)if one of the DAAs requires pharmacokinetic enhancement. The two DAAscan be administered concurrently or sequentially. For example, one DAAcan be administered once daily, and the other DAA can be administeredtwice daily. For another example, the two DAAs are administered oncedaily. For yet another example, the two DAAs are co-formulated in asingle composition and administered concurrently (e.g., once daily). Asa non-limiting example, the patient being treated can be infected withHCV genotype 1, such as genotype 1a or 1b. As another non-limitingexample, the patient can be infected with HCV genotype 2 or 3. As yetanother non-limiting example, the patient can be a HCV-treatment naïvepatient, a HCV-treatment experienced patient, an interferonnon-responder (e.g., a null responder), or not a candidate forinterferon treatment. In one example, the treatment lasts for 16 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In another example, the treatment lasts for 15 weeks, andthe subject being treated is a naïve patient infected with HCVgenotype 1. In still another example, the treatment lasts for 14 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 13 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 1. In yet another example, the treatment lasts for 12 weeks,and the subject being treated is a naïve patient infected with HCVgenotype 2. In another example, the treatment lasts for 11 weeks, andthe subject being treated is a naïve patient infected with HCV genotype2. In still another example, the treatment lasts for 10 weeks, and thesubject being treated is a naïve patient infected with HCV genotype 2.In yet another example, the treatment lasts for 9 weeks, and the subjectbeing treated is a naïve patient infected with HCV genotype 2. In yetanother example, the treatment lasts for 8 weeks, and the subject beingtreated is a naïve patient infected with HCV genotype 2. In yet anotherexample, the treatment lasts for 16 weeks, and the subject being treatedis a naïve patient infected with HCV genotype 3. In another example, thetreatment lasts for 15 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In still another example, thetreatment lasts for 14 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 13 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 12 weeks, and the subject being treated is a naïvepatient infected with HCV genotype 3. In yet another example, thetreatment lasts for 16 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inanother example, the treatment lasts for 15 weeks, and the subject beingtreated is a non-responder (e.g., a null responder) infected with HCVgenotype 1. In still another example, the treatment lasts for 14 weeks,and the subject being treated is a non-responder (e.g., a nullresponder) infected with HCV genotype 1. In yet another example, thetreatment lasts for 13 weeks, and the subject being treated is anon-responder (e.g., a null responder) infected with HCV genotype 1. Inyet another example, the treatment lasts for 12 weeks, and the subjectbeing treated is a non-responder (e.g., a null responder) infected withHCV genotype 1.

In another aspect, the present invention features methods for treatmentof HCV infection, wherein the methods comprise administering to asubject in need thereof at least two direct acting antiviral agents(DAAs) and ribavirin, and the treatment does not include administrationof interferon to the subject. The treatment can last, for example andwithout limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or12 weeks. Preferably, the treatment lasts for 12 weeks. The treatmentcan also last for 8 weeks. The subject being treated can be, forexample, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In one embodiment of this aspect of the invention, the at least two DAAscomprise (i) Compound 1 or a pharmaceutically acceptable salt thereof,and (ii) Compound 2 or a pharmaceutically acceptable salt thereof, andsaid method further comprises administering ritonavir to the subject.Ritonavir improves the pharmacokinetics or drug exposure of Compound 1.The treatment can last, for example and without limitation, for no morethan 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, thetreatment lasts for 12 weeks. The treatment can also last for 8 weeks.The subject being treated can be, for example, a treatment-naïvepatient. The subject can also be a treatment-experienced patient, or aninterferon non-responder (e.g., a null responder). Preferably, thesubject being treated is infected with HCV genotype 1, e.g., HCVgenotype 1a. As another non-limiting example, the subject beingtreatment is infected with HCV genotype 3.

In another embodiment of this aspect of the invention, the at least twoDAAs comprise (i) Compound 1 or a pharmaceutically acceptable saltthereof, and (ii) Compound 4 or a pharmaceutically acceptable saltthereof, and the method further comprises administering ritonavir to thesubject to improve the pharmacokinetics or drug exposure of Compound 1.The treatment can last, for example and without limitation, for no morethan 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, thetreatment lasts for 12 weeks. The treatment can also last for 8 weeks.The subject being treated can be, for example, a treatment-naïvepatient. The subject can also be a treatment-experienced patient, or aninterferon non-responder (e.g., a null responder). Preferably, thesubject being treated is infected with HCV genotype 1, e.g., HCVgenotype 1a. As another non-limiting example, the subject beingtreatment is infected with HCV genotype 3.

In another embodiment of this aspect of the invention, the at least twoDAAs comprise (i) Compound 1 or a pharmaceutically acceptable saltthereof, (ii) Compound 2 or a pharmaceutically acceptable salt thereof,and (iii) Compound 4 or a pharmaceutically acceptable salt thereof, andthe method further comprises administering ritonavir to the subject toimprove the pharmacokinetics or drug exposure of Compound 1. Thetreatment can last, for example and without limitation, for no more than12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatmentlasts for 12 weeks. The treatment can also last for 8 weeks. The subjectbeing treated can be, for example, a treatment-naïve patient. Thesubject can also be a treatment-experienced patient, or an interferonnon-responder (e.g., a null responder). Preferably, the subject beingtreated is infected with HCV genotype 1, e.g., HCV genotype 1a. Asanother non-limiting example, the subject being treatment is infectedwith HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV protease inhibitor and a HCV polymeraseinhibitor. The treatment can last, for example and without limitation,for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably,the treatment lasts for 12 weeks. The treatment can also last for 8weeks. The subject being treated can be, for example, a treatment-naïvepatient. The subject can also be a treatment-experienced patient, or aninterferon non-responder (e.g., a null responder). Preferably, thesubject being treated is infected with HCV genotype 1, e.g., HCVgenotype 1a. As another non-limiting example, the subject beingtreatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV protease inhibitor and a non-nucleoside ornon-nucleotide HCV polymerase inhibitor. The treatment can last, forexample and without limitation, for no more than 12 weeks, such as 8, 9,10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. Thetreatment can also last for 8 weeks. The subject being treated can be,for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV protease inhibitor and a nucleoside ornucleotide HCV polymerase inhibitor. The treatment can last, for exampleand without limitation, for no more than 12 weeks, such as 8, 9, 10, 11or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatmentcan also last for 8 weeks. The subject being treated can be, forexample, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV protease inhibitor and a HCV NS5A inhibitor. Thetreatment can last, for example and without limitation, for no more than12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatmentlasts for 12 weeks. The treatment can also last for 8 weeks. The subjectbeing treated can be, for example, a treatment-naïve patient. Thesubject can also be a treatment-experienced patient, or an interferonnon-responder (e.g., a null responder). Preferably, the subject beingtreated is infected with HCV genotype 1, e.g., HCV genotype 1a. Asanother non-limiting example, the subject being treatment is infectedwith HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV polymerase inhibitor and a HCV NS5A inhibitor.The treatment can last, for example and without limitation, for no morethan 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, thetreatment lasts for 12 weeks. The treatment can also last for 8 weeks.The subject being treated can be, for example, a treatment-naïvepatient. The subject can also be a treatment-experienced patient, or aninterferon non-responder (e.g., a null responder). Preferably, thesubject being treated is infected with HCV genotype 1, e.g., HCVgenotype 1a. As another non-limiting example, the subject beingtreatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV non-nucleoside or non-nucleotide polymeraseinhibitor and a HCV NS5A inhibitor. The treatment can last, for exampleand without limitation, for no more than 12 weeks, such as 8, 9, 10, 11or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatmentcan also last for 8 weeks. The subject being treated can be, forexample, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise a HCV nucleoside or nucleotide polymerase inhibitorand a HCV NS5A inhibitor. The treatment can last, for example andwithout limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or12 weeks. Preferably, the treatment lasts for 12 weeks. The treatmentcan also last for 8 weeks. The subject being treated can be, forexample, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise PSI-7977 and TMC-435. The treatment can last, forexample and without limitation, for no more than 12 weeks, such as 8, 9,10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. Thetreatment can also last for 8 weeks. The subject being treated can be,for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise PSI-7977 and daclatasvir. The treatment can last, forexample and without limitation, for no more than 12 weeks, such as 8, 9,10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. Thetreatment can also last for 8 weeks. The subject being treated can be,for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise PSI-7977 and GS-5885. The treatment can last, forexample and without limitation, for no more than 12 weeks, such as 8, 9,10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. Thetreatment can also last for 8 weeks. The subject being treated can be,for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise mericitabine and danoprevir. The treatment can last,for example and without limitation, for no more than 12 weeks, such as8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.The treatment can also last for 8 weeks. The subject being treated canbe, for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example,the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise BMS-790052 and BMS-650032. The treatment can last, forexample and without limitation, for no more than 12 weeks, such as 8, 9,10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. Thetreatment can also last for 8 weeks. The subject being treated can be,for example, a treatment-naïve patient. The subject can also be atreatment-experienced patient, or an interferon non-responder (e.g., anull responder). Preferably, the subject being treated is infected withHCV genotype 1, e.g., HCV genotype 1b. As a non-limiting example, thesubject being treatment is infected with HCV genotype 1a. As anothernon-limiting example, the subject being treatment is infected with HCVgenotype 3.

In yet another embodiment of this aspect of the invention, the at leasttwo DAAs comprise INX-189, daclatasvir and BMS-791325. The treatment canlast, for example and without limitation, for no more than 12 weeks,such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12weeks. The treatment can also last for 8 weeks. The subject beingtreated can be, for example, a treatment-naïve patient. The subject canalso be a treatment-experienced patient, or an interferon non-responder(e.g., a null responder). Preferably, the subject being treated isinfected with HCV genotype 1, e.g., HCV genotype 1a. As anothernon-limiting example, the subject being treatment is infected with HCVgenotype 3.

In yet another aspect, the present invention features methods fortreatment of a treatment-naïve subject with HCV genotype 1 infection,wherein the method comprises administering to said patient PSI-7977 andribavirin, and the treatment does not include administration ofinterferon to the subject. The treatment can last, for example andwithout limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or12 weeks. Preferably, the treatment lasts for 12 weeks. The treatmentcan also last for 8 weeks. Preferably, the subject being treated isinfected with genotype 1a. More preferably, the subject being treated isa naïve patient infected with genotype 1. The subject being treated canalso be a treatment-experienced patient or an interferon non-responder(e.g., a null responder), and/or is infected with HCV genotype 3. In oneexample, the treatment lasts for 12 weeks, and the subject being treatedis a naïve patient infected with genotype 1. In another example, thetreatment lasts for 11 weeks, and the subject being treated is a naïvepatient infected with genotype 1. In still another example, thetreatment lasts for 10 weeks, and the subject being treated is a naïvepatient infected with genotype 1. In yet another example, the treatmentlasts for 9 weeks, and the subject being treated is a naïve patientinfected with genotype 1. In yet another example, the treatment lastsfor 8 weeks, and the subject being treated is a naïve patient infectedwith genotype 1. The present invention also features PSI-7977 or apharmaceutical acceptable salt thereof for use in any treatmentdescribed in this aspect of the invention.

A treatment regimen of the present technology generally constitutes acomplete treatment regimen, i.e., no subsequent interferon-containingregimen is intended. Thus, a treatment or use described herein generallydoes not include any subsequent interferon-containing treatment.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, not limitation.

Various changes and modifications within the scope of the invention willbecome apparent to those skilled in the art from the detaileddescription

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a 3-D surface plot illustrating deviations from expectedinhibitory effects from varying concentrations of Compound 1 andCompound 2 in a genotype 1b HCV replicon assay.

FIG. 2 is a contour plot showing concentrations at which Compound 1 andCompound 2 exhibited syngeristic, additive, or antagonistic interactionsin the genotype 1b HCV replicon assay.

FIG. 3 is a 3-D surface plot illustrating deviations from expectedinhibitory effects from varying concentrations of Compound 1 andcompound 4 in a genotype 1b HCV replicon assay.

FIG. 4 is a contour plot showing concentrations at which Compound 1 andcompound 4 exhibited syngeristic, additive, or antagonistic interactionsin the genotype 1b HCV replicon assay.

FIG. 5A is a bar graph showing the percentage of cells containing HCVgenotype 1a replicon constructs surviving after three weeks of exposureto therapeutic agent 1, therapeutic agent 2, therapeutic agent 4, or acombination of some or all of those therapeutic agents in the presenceof G418.

FIG. 5B is another bar graph showing the percentage of surviving 1a-H77replicon cells grown in the presence of G418, and two or three DAAcombinations, for approximately three weeks.

FIG. 5C depicts the effect of Compound 1, Compound 2 and a combinationthereof in long-term HCV RNA reduction assays in 1a-H77 replicon celllines.

FIG. 5D demonstrates the effect of Compound 1, Compound 2 and acombination thereof in long-term HCV RNA reduction assays in 1b-Con1replicon cell lines.

FIG. 6A shows the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 2-DAA regimen withoutribavirin; the 2 DAAs include (i) Compound 1 with ritonavir (Compound1/r) and (ii) Compound 2.

FIG. 6B illustrates the predicted median and 90% confidence interval ofSVR percentage for different treatment durations of a 2-DAA regimenwithout ribavirin; the 2 DAAs include (i) Compound 1 with ritonavir(Compound 1/r) and (ii) Compound 4.

FIG. 6C depicts the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 3-DAA regimen withoutribavirin; the 3 DAAs include (i) Compound 1 with ritonavir (Compound1/r), (ii) Compound 2 and (iii) Compound 4.

FIG. 7 shows the exposure-response model predicted versus observedpercentage of subjects with HCV RNA less than LOD over time in theclinical study described in Example 1.

FIG. 8 demonstrates the exposure-response model predicted versusobserved percentage of subjects with SVR12 in the clinical studydescribed in Example 2A.

FIG. 9 shows the predicted median and 90% confidence interval of SVRrates for different treatment durations of a 2-DAA regimen containingBMS-790052 and BMS-650032.

FIG. 10 shows the predicted median of SVR rates for different treatmentdurations of a 3-DAA regimen containing Compound 1/r, Compound 4 andPSI-7977.

FIG. 11 shows the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 1-DAA regimencontaining PSI-7977 and ribavirin.

FIG. 12 depicts the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 2-DAA regimencontaining daclatasvir (BMS-790052) 60 mg QD and PSI-7977 400 mg QD.

FIG. 13 shows the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 2-DAA regimencontaining TMC-435 150 mg QD and PSI-7977 400 mg QD.

FIG. 14 illustrates the predicted median and 90% confidence interval ofSVR percentage for different treatment durations of a 2-DAA regimencontaining danoprevir 100 mg BID and mercitabine 750 mg BID.

FIG. 15 depicts the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of a 2-DAA regimencontaining GS-9190 (tegobuvir) 30 mg BID+GS-9451 200 mg QD+GS-5885 90 mgQD.

FIG. 16 shows the predicted median and 90% confidence interval of SVRpercentage for different treatment durations of the following DAA comboregimens: (1) GS-9451 200 mg QD+GS-7977 (PSI-7977) 400 mg QD; (2)GS-5885 90 mg QD+GS-7977 (PSI-7977) 400 mg QD; and (3) GS-9451 200 mgQD+GS-5885 90 mg QD+GS-7977 (PSI-7977) 400 mg QD.

DETAILED DESCRIPTION OF THE INVENTION

The present methods can include administering therapeutic agent 1 to asubject. Therapeutic agent 1 is Compound 1

or a pharmaceutically acceptable salt thereof. Compound 1 is also knownas(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide.Compound 1 is a potent HCV protease inhibitor. The synthesis andformulation of Compound 1 are described in U.S. Patent ApplicationPublication No. 2010/0144608, U.S. Provisional Application Ser. No.61/339,964 filed on Mar. 10, 2010, and U.S. Patent ApplicationPublication No. 2011/0312973 filed on Mar. 8, 2011. All of theseapplications are incorporated herein by reference in their entireties.Therapeutic agent 1 includes various salts of Compound 1. Therapeuticagent 1 may be administered in any suitable amount such as, for example,in doses of from about 0.01 to about 50 mg/kg body weight, alternativelyfrom about 0.1 to about 25 mg/kg body weight. As non-limiting examples,therapeutic agent 1 may be administered in a total daily dose amount offrom about 50 mg to about 250 mg, preferably from about 100 mg to about250 mg, and includes, but is not limited to, for example, about 50 mg,about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg and suitable amounts therebetween.

In preferred embodiments, ritonavir or another inhibitor of cytochromeP-450 is co-administered with therapeutic agent 1 to improve thepharmacokinetics of Compound 1.

The present methods can include administering therapeutic agent 2 to asubject. Therapeutic agent 2 is Compound 2 or a salt thereof.

Compound 2 is also knownN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.As described in, for example, International Publication No.WO2009/039127, therapeutic agent 2 includes various salts of Compound 2,such as sodium salts, potassium salts, and choline salts. Therapeuticagent 2 also includes crystalline forms of Compound 2 and its salts suchas solvate, hydrate, and solvent-free crystalline forms of Compound 2and its salts. Compositions comprising therapeutic agent 2 can beprepared as described in, for example, International Publication No.WO2009/039127 which is incorporated by reference herein.

Therapeutic agent 2 may be administered as a free acid, salt orparticular crystalline form of Compound 2. In some embodiments,therapeutic agent 2 is administered as a sodium salt. Therapeutic agent2 may be administered in any suitable amount such as, for example, indoses of from about 5 mg/kg to about 30 mg/kg. As non-limiting examples,therapeutic agent 2 may be administered in a total daily dose amount offrom about 300 mg to about 1800 mg, or from about 400 mg to about 1600mg, or from about 600 mg to about 1800 mg, or from about 800 mg to about1600 mg or any amounts there between. In some embodiments, the totaldaily dosage amount for therapeutic agent 2 is about 600 mg. In someembodiments, the total daily dosage amount for therapeutic agent 2 isabout 800 mg. In some embodiments, the total daily dosage amount fortherapeutic agent 2 is about 1200 mg. In some embodiments, the totaldaily dosage amount for therapeutic agent 2 is about 1600 mg.

The present methods can include administering therapeutic agent 3 or asalt thereof to a subject. Therapeutic agent 3 is Compound 3 or a saltthereof.

Compound 3 is also known as(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyryl)phenyl)methanesulfonamide.As described in, for example, International Publication No.WO2009/039127, therapeutic agent 3 includes various salts of Compound 3,such as sodium salts, potassium salts, and choline salts. Therapeuticagent 3 also includes crystalline forms of Compound 3 and its salts suchas solvate, hydrate, and solvent-free crystalline forms of Compound 3and its salts. Compositions comprising therapeutic agent 3 can beprepared as described in, for example, International Publication No.WO2009/039127 which is incorporated by reference herein.

Therapeutic agent 3 may be administered as a free acid, salt orparticular crystalline form of Compound 3. In some embodiments, Compound3 is administered as a potassium salt. Therapeutic agent 3 may beadministered in any suitable amount such as, for example, in doses offrom about 0.5 mg/kg to about 15 mg/kg or from about 1 mg/kg to about 10mg/kg. As non-limiting examples, therapeutic agent 3 may be administeredin a total daily dose amount of from about 100 mg to about 600 mg. Insome embodiments, the total daily dosage amount for therapeutic agent 3is about 300 mg. In some embodiments, the total daily dosage amount fortherapeutic agent 3 is about 320 mg. In some embodiments, the totaldaily dosage amount for therapeutic agent 3 is about 400 mg. In someembodiments, the total daily dosage amount for therapeutic agent 3 isabout 600 mg.

The present methods can include administering therapeutic agent 4 or asalt thereof to a subject. Therapeutic agent 4 is compound 4 or a saltthereof.

Compound 4 is also known as dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5,diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl)bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate.Compound 4 can be prepared as described in, for example, U.S.Publication No. 2010/0317568, which is incorporated herein by reference.

Therapeutic agent 4 may be administered as a free acid, or a salt form.Therapeutic agent 4 may be administered in any suitable amount such as,for example, in doses of from about 0.1 mg/kg to about 200 mg/kg bodyweight, or from about 0.25 mg/kg to about 100 mg/kg, or from about 0.3mg/kg to about 30 mg/kg. As non-limiting examples, therapeutic agent 4may be administered in a total daily dose amount of from about 5 mg toabout 300 mg, or from about 25 mg to about 200 mg, or from about 25 mgto about 50 mg or any amounts there between. In some embodiments, thetotal daily dosage amount for therapeutic agent 4 is about 25 mg.

The at least two DAAs may also be co-administered with ribavirin, or apro-drug thereof, in the same or separate pharmaceutical compositions.Ribavirin may include any suitable form or formulation of ribavirin.Exemplary formulations of ribavirin include COPEGUS®, REBETOL® andRIBASPHERE®. An exemplary pro-drug of ribavirin is taribavirin havingthe chemical name of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine.Ribavirin and taribavirin may be administered in accordance withribavirin and taribavirin administration well known in the art. In someembodiments, COPEGUS® or REBETOL® is administered in a daily dosageamount of from about 500 mg to about 1500 mg in one dose or in divideddoses. In some embodiments, COPEGUS® or REBETOL® is administered in adaily dosage amount of about 800 mg. In some embodiments, REBETOL® isadministered in a daily dosage amount of about 1000 mg. In someembodiments, COPEGUS® or REBETOL® is administered in a daily dosageamount of about 1200 mg. In some embodiments, REBETOL® is administeredin a daily dosage amount of about 1400 mg. Suitable dosages of ribavirinare dependent on the weight of the subject, for example about 1000-1200mg. Suitable total daily dosages of ribavirin include, but are notlimited to about 400 mg to about 1400 mg a day, alternatively about 800mg to about 1400 mg per day, alternatively about 400 mg to about 1200mg, alternatively about 800 mg to about 1200 mg.

The current standard of care (SOC) for the treatment of HCV includes acourse of treatment of interferon, e.g. pegylated interferon (e.g.,pegylated interferon-alpha-2a or pegylated interferon-alpha-2b, such asPEGASYS by Roche, or PEG-INTRON by Schering-Plough) and the antiviraldrug ribavirin (e.g., COPEGUS by Roche, REBETOL by Schering-Plough, orRIBASPHERE by Three Rivers Pharmaceuticals). The treatment often lastsfor 24-48 weeks, depending on hepatitis C virus genotype. Otherinterferons include, but are not limited to, interferon-alpha-2a (e.g.,Roferon-A by Roche), interferon-alpha-2b (e.g., Intron-A bySchering-Plough), and interferon alfacon-1 (consensus interferon) (e.g.,Infergen by Valeant). Less than 50% of patients with chronic HCVinfection with genotype 1 virus respond to this therapy. Further,interferon therapy has many side effects that hinder patient complianceand results in premature discontinuation of the treatment.

The interferon/ribavirin-based treatment may be physically demanding,and can lead to temporary disability in some cases. A substantialproportion of patients will experience a panoply of side effects rangingfrom a “flu-like” syndrome (the most common, experienced for a few daysafter the weekly injection of interferon) to severe adverse eventsincluding anemia, cardiovascular events and psychiatric problems such assuicide or suicidal ideation. The latter are exacerbated by the generalphysiological stress experienced by the patients. Ribavirin also has anumber of side effects, including, anemia, high pill burden (e.g. 5-6pills a day split BID) and teratogenicity restricting use in women ofchildbearing age.

The present methods provide effective treatment of HCV infection withoutthe use of interferon and for a shorter period of time, such as atreatment duration of no more than twelve weeks, alternatively no morethan eleven weeks, alternatively no more than ten weeks, alternativelyno more than nine weeks, alternatively no more than eight weeks,alternatively no more than seven weeks, alternatively no more than sixweeks, alternatively no more than five weeks, alternatively no more thanfour weeks, or alternatively, no more than three weeks.

In some embodiments, the present technology provides methods fortreating HCV infection in a subject comprising administering at leasttwo DAAs with ribavirin in the absence of interferon for a duration ofno more than twelve weeks, alternatively no more than eight weeks. Putanother way, the present methods exclude interferon, or the subject doesnot receive interferon for the duration of the treatment. The at leasttwo DAAs can be co-administered or can be administered independently(with the same or different dosing frequencies) and can be administeredonce a day, alternatively twice a day, alternatively three times a day.

In some embodiments, the methods of treatment comprise dailyadministration of two or more DAAs, wherein a first DAA may beadministered once a day, twice a day, or three times a day, and a secondDAA may be administered once a day, twice a day, or three times a day.In some embodiments, a third DAA may be administered once a day, twice aday, or three times a day. The DAAs may be co-administered oradministered at different times or frequencies. Preferably, in themethods, at least two DAAs and ribavirin are administered in effectiveamounts to provide a desired measure of effectiveness in the subject.Preferably, the treatment has reduced side effects as compared withinterferon-containing treatments.

Various measures may be used to express the effectiveness of the presentmethods of HCV treatment. One such measure is rapid virological response(RVR), meaning that HCV is undetectable in the subject after 4 weeks oftreatment, for example, after 4 weeks of administration of two or moreof DAAs and ribavirin. Another measure is early virological response(EVR), meaning that the subject has ≧2 log₁₀ reduction in viral loadafter 12 weeks of treatment. Another measure is complete EVR (cEVR),meaning the HCV is undetectable in the serum of the subject after 12weeks of treatment. Another measure is extended RVR (eRVR), meaningachievement of RVR and cEVR, that is, HCV is undetectable at week 4 and12. Another measure is the presence or absence of detectable virus atthe end of therapy (EOT). Another measure is (SVR), which, as usedherein, means that the virus is undetectable at the end of therapy andfor at least 8 weeks after the end of therapy (SVR8); preferably, thevirus is undetectable at the end of therapy and for at least 12 weeksafter the end of therapy (SVR12); more preferably, the virus isundetectable at the end of therapy and for at least 16 weeks after theend of therapy (SVR16); and highly preferably, the virus is undetectableat the end of therapy and for at least 24 weeks after the end of therapy(SVR24). SVR24 is often considered as a functional definition of cure;and a high rate of SVR at less than 24 week post-treatment (e.g., SVR8or SVR12) can be predictive of a high rate of SVR24. Likewise, a highrate of SVR at less than 12 week post-treatment (e.g., SVR4 or SVR8) canbe predictive of a high rate of SVR12. A high rate of EOT (e.g., at week8 or week 12) can also be indicative of a significant rate of SVR12 orSVR24.

In some embodiments, the amounts of the two or more DAAs and ribavirin,and/or the duration of the treatment regimen of the two or more DAAs andribavirin, are effective to provide an RVR in a subject, or an EVR in asubject, or a cEVR in a subject, or an eRVR in a subject, or an absenceof detectable virus at EOT in a subject. In some embodiments, thepresent methods comprise treating a population of subjects having HCVinfection (e.g. treatment naïve subjects), and the methods compriseadministering at least two DAAs and ribavirin to the subjects for aduration of no more than 12 weeks, or for another duration disclosedherein, wherein the at least two DAAs and ribavirin are administered tothe subjects in amounts effective to provide an SVR (e.g., SVR after 8weeks post-treatment, or SVR after 24 weeks post-treatment) in at leastabout 70% of the population, alternatively at least about 75% of thepopulation, alternatively at least about 80% of the population,alternatively at least about 85% of the population, alternatively atleast about 90% of the population, alternatively at least about 95% ofthe population, alternatively about 100% of the population. In someembodiments, the present methods comprise treating a population of IFNexperienced subjects (e.g., interferon non-responders) having HCVinfection, and the methods comprise administering at least two DAAs andribavirin to the subjects for a duration of no more than 12 weeks, orfor another duration disclosed herein, wherein the at least two DAAs andribavirin are administered to the subjects in amounts effective toprovide an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after 24weeks post-treatment) in at least about 50% of the population,alternatively at least about 55% of the population, alternatively atleast about 60% of the population, alternatively at least about 65% ofthe population. In other embodiments, the amount of DAAs and ribavirinand the duration of the treatment are effective to provide one or moreof an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after 24 weekspost-treatment), an RVR, an EVR, a cEVR, an eRVR, or an absence ofdetectable virus at EOT, in at least about 50% of the population,alternatively at least about 55%, in at least about 60% of thepopulation, alternatively at least about 65% of the population,alternatively at least about 70% of the population, alternatively atleast about 75% of the population, alternatively at least about 80% ofthe population, alternatively at least about 85% of the population,alternatively at least about 90% of the population, alternatively atleast about 95% of the population, alternatively about 100% of thepopulation. For example, the present methods comprise administering atleast two DAAs and ribavirin in amounts and for durations effective toprovide an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after 24weeks post-treatment) in a subject. In some embodiments, the presenttechnology provides for an SVR (e.g., SVR after 8 weeks post-treatment,or SVR after 24 weeks post-treatment) in at least about 50% of thepopulation, alternatively at least about 55% of the population, in atleast about 60% of the population, preferably in at least about 65% ofthe population, preferably in at least about 70% of the population,preferably at least about 75% of the patients treated by such methodsherein described, more preferably in at least 80% of the population, andhighly preferably in at least about 90% of the patients being treated.In some embodiments, a treatment of the present technology provides anRVR or undetectable level of HCV RNA in the bloodstream at four (4)weeks of treatment (preferably in addition to a SVR).

A DAA of the present technology includes, but is not limited to, aprotease inhibitor, a HCV polymerase inhibitor, an HCV NS5A inhibitor,an HCV NS3B inhibitor, an HCV NS4A inhibitor, an HCV NS5B inhibitor, anHCV entry inhibitor, a cyclophilin inhibitor, a CD81 inhibitor, or aninternal ribosome entry site inhibitor. The HCV polymerase inhibitor maybe a nucleoside polymerase inhibitor or a non-nucleoside polymeraseinhibitor. The HCV polymerase inhibitor may be a nucleotide polymeraseinhibitor or a non-nucleotide polymerase inhibitor.

In yet another example of this aspect of the technology, the combinationof two or more DAAs comprises PSI-7977 and PSI-938. In yet anotherexample, the combination of two or more DAAs comprises PSI-7977 andTMC-435. In yet another example, the combination of two or more DAAscomprises BMS-790052 and BMS-650032. In yet another example, thecombination of two or more DAAs comprises GS-5885, GS-9190, and GS-9451.In yet another example, the combination of two or more DAAs comprisesBI-201335 and BI-207127. In yet another example, the combination of twoor more DAAs comprises telaprevir and VX-222. In another example, thecombination of two or more DAAs comprises GS-5885 and GS-9451. In yetanother example, the combination of two or more DAAs includes danoprevir(with ritonavir) and R7128. In yet another example, the combination oftwo or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In yetanother example, the combination of two or more DAAs includes PSI-7977and BMS-650032 (asunaprevir). In still another example, the combinationof two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In another example, the combination of two ormore DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir).

It was unexpectedly discovered that an interferon-free treatment using acombination of two or more DAAs, together with ribavirin, and for aduration of no more than 12 weeks, could achieve significant SVR. Inmany cases, such a treatment can achieve an SVR in at least about 75% ofpatients, and in some cases, such a treatment can achieve an SVR in atleast about 85% of patients, and in certain cases, such a treatment canachieve an SVR in at least about 90% of patients. It was also surprisingthat such a treatment could achieve significant viral suppression evenat 4 weeks of the treatment. In some embodiments, the interferon-freetreatment using a combination of two or more DAAs, together withribavirin, and for a duration of no more than 12 weeks, could achievesignificant SVR in interferon non-responders, for example, treatment canachieve an SVR in at least about 50% of patients in the interferonnon-responder population, preferably at least about 60% of patients inthe interferon non-responder population, more preferably at least about65% of patients in the interferon non-responder population.

Accordingly, in one aspect, the present technology features a method oftreating HCV infection, comprising administering to a patient in needthereof an effective amount of a combination of two or more DAAs,together with an effective amount of ribavirin. The treatment lasts 8weeks and does not include administration of any interferon. The DAAsand ribavirin can be administered at the same or different dosingfrequencies. The patient being treated can be a treatment naïve patient,a treatment experienced patient, including, but not limited to, arelapser, an interferon partial responder, an interferon non-responder(e.g., a null responder), or a patient unable to take interferon. Thepatient may be infected with, for example and without limitation, HCVgenotype 1, such as HCV genotype 1a or HCV genotype 1b; or HCV genotype2 or 3. The treatment according to this aspect of the technology mayalso be effective against other HCV genotypes. The DAAs can beadministered around the same time or at different times, and can beco-formulated in a single formulation or formulated in differentcompositions. Each DAA can be selected from HCV protease inhibitors, HCVpolymerase inhibitors, or HCV NS5A inhibitors. For instance, thecombination of two or more DAAs can be a combination of at least one HCVprotease inhibitor and at least one HCV polymerase inhibitor (e.g., acombination of at least one HCV protease inhibitor and at least onenon-nucleoside polymerase inhibitor, or a combination of at least oneHCV protease inhibitor and at least one nucleoside or nucleotidepolymerase inhibitor, or a combination of at least one HCV proteaseinhibitor, at least one nucleoside or nucleotide polymerase inhibitorand at least one non-nucleoside inhibitor). For another instance, thecombination of two or more DAAs can be a combination of at least one HCVprotease inhibitor and at least one HCV NS5A inhibitor. For stillanother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor, at least one HCVpolymerase inhibitor, and at least one HCV NS5A inhibitor. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV polymerase inhibitors (e.g., a combination of at least twonucleoside polymerase inhibitors, or a combination of at least onenucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside or nucleotide polymerase inhibitor, or a combination ofat least two non-nucleoside polymerase inhibitors). For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV protease inhibitors. For another instance, the combinationof two or more DAAs can be a combination of at least two HCV NS5Ainhibitors. For another instance, the combination of two or more DAAscan be a combination of at least one HCV polymerase inhibitor and atleast one NS5A inhibitor (e.g., a combination of at least one HCV NS5Ainhibitor and at least one non-nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor and atleast one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor, at least one nucleosideor nucleotide polymerase inhibitor and at least one non-nucleosidepolymerase inhibitor). In one example, the combination of two or moreDAAs is a combination of Compound 1 (or a salt thereof) and Compound 2(or a salt thereof). Compound 1 (or a salt thereof) can be co-formulatedwith ritonavir. In another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 3 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 can be co-formulated with ritonavir. In yet anotherexample, the combination of two or more DAAs comprises PSI-7977 andPSI-938. In yet another example, the combination of two or more DAAscomprises PSI-7977 and TMC-435. In yet another example, the combinationof two or more DAAs comprises BMS-790052 and BMS-650032. In yet anotherexample, the combination of two or more DAAs comprises GS-5885, GS-9190,and GS-9451. In yet another example, the combination of two or more DAAscomprises BI-201335 and BI-207127. In yet another example, thecombination of two or more DAAs comprises telaprevir and VX-222. Inanother example, the combination of two or more DAAs comprises GS-5885and GS-9451. In yet another example, the combination of two or more DAAsincludes danoprevir (with ritonavir) and R7128. In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still anotherexample, the combination of two or more DAAs includes PSI-7977,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-790052 (daclatasvir). In yet another example, the combination of twoor more DAAs includes INX-189 and BMS-650032 (asunaprevir). In stillanother example, the combination of two or more DAAs includes INX-189,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still anotherexample, the combination of two or more DAAs includes mericitabine anddanoprevir. In still another example, the combination of two or moreDAAs includes INX-189, daclatasvir and BMS-791325. In still anotherexample, the combination of two or more DAAs includes PSI-7977 andGS-5885. In still another example, the combination of two or more DAAsincludes PSI-7977, Compound 1 (with ritonavir), and Compound 4. In stillanother example, the method comprises administering to a patient in needthereof an effective amount of PSI-7977 as the sole DAA in lieu of acombination of two or more DAAs, together with an effective amount ofribavirin. In still another example, the method comprises administering100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and25 mg compound 4 once daily. In yet another example, the methodcomprises administering 150 mg or 250 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 2 twice daily. In anotherexample, the method comprises administering 150 mg Compound 1 togetherwith 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. Inanother example, the method comprises administering 150 mg Compound 1together with 100 mg ritonavir once daily, and 400 mg Compound 3 twicedaily. In another example, the method comprises administering 100 or 150mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound4 once daily, and 400 mg Compound 2 twice daily. In another example, themethod comprises administering 100 or 150 mg Compound 1 together with100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mgCompound 3 twice daily. Ribavirin can be administered based on patientweight, and in many cases, 1000 to 1200 mg divided twice daily. OtherDAA(s) can also be included in a treatment regimen according to thisaspect of the technology.

In another aspect, the present technology features a method of treatingHCV, comprising administering to a patient in need thereof an effectiveamount of a combination of two or more DAAs, together with an effectiveamount of ribavirin. The treatment lasts 7 weeks and does not includeadministration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside or nucleotide polymeraseinhibitors, or a combination of at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least two non-nucleoside polymeraseinhibitors). For another instance, the combination of two or more DAAscan be a combination of at least two HCV protease inhibitors. Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV NS5A inhibitors. For another instance,the combination of two or more DAAs can be a combination of at least oneHCV polymerase inhibitor and at least one NS5A inhibitor (e.g., acombination of at least one HCV NS5A inhibitor and at least onenon-nucleoside polymerase inhibitor, or a combination of at least oneHCV NS5A inhibitor and at least one nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor, at leastone nucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor). In one example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 2 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In another example, the combination of twoor more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 3 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In still another example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof)and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) canbe co-formulated with ritonavir. In a further example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof),Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).Compound 1 (or a salt thereof) can be co-formulated with ritonavir. Inyet another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof), Compound 3 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs comprises PSI-7977 and PSI-938. Inyet another example, the combination of two or more DAAs comprisesPSI-7977 and TMC-435. In yet another example, the combination of two ormore DAAs comprises BMS-790052 and BMS-650032. In yet another example,the combination of two or more DAAs comprises GS-5885, GS-9190, andGS-9451. In yet another example, the combination of two or more DAAscomprises BI-201335 and BI-207127. In yet another example, thecombination of two or more DAAs comprises telaprevir and VX-222. Inanother example, the combination of two or more DAAs comprises GS-5885and GS-9451. In yet another example, the combination of two or more DAAsincludes danoprevir (with ritonavir) and R7128. In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still anotherexample, the combination of two or more DAAs includes PSI-7977,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-790052 (daclatasvir). In yet another example, the combination of twoor more DAAs includes INX-189 and BMS-650032 (asunaprevir). In stillanother example, the combination of two or more DAAs includes INX-189,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still anotherexample, the combination of two or more DAAs includes mericitabine anddanoprevir. In still another example, the combination of two or moreDAAs includes INX-189, daclatasvir and BMS-791325. In still anotherexample, the combination of two or more DAAs includes PSI-7977 andGS-5885. In still another example, the combination of two or more DAAsincludes PSI-7977, Compound 1 (with ritonavir), and Compound 4. In stillanother example, the method comprises administering to a patient in needthereof an effective amount of PSI-7977 as the sole DAA in lieu of acombination of two or more DAAs, together with an effective amount ofribavirin. In still another example, the method comprises administering100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and25 mg compound 4 once daily. In yet another example, the methodcomprises administering 150 mg or 250 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 2 twice daily. In anotherexample, the method comprises administering 150 mg Compound 1 togetherwith 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. Inanother example, the method comprises administering 150 mg Compound 1together with 100 mg ritonavir once daily, and 400 mg Compound 3 twicedaily. In another example, the method comprises administering 100 or 150mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound4 once daily, and 400 mg Compound 2 twice daily. In another example, themethod comprises administering 100 or 150 mg Compound 1 together with100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mgCompound 3 twice daily. Ribavirin can be administered based on patientweight, and in many cases, 1000 to 1200 mg divided twice daily. OtherDAA(s) can also be included in a treatment regimen according to thisaspect of the technology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 6 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside or nucleotide polymeraseinhibitors, or a combination of at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least two non-nucleoside polymeraseinhibitors). For another instance, the combination of two or more DAAscan be a combination of at least two HCV protease inhibitors. Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV NS5A inhibitors. For another instance,the combination of two or more DAAs can be a combination of at least oneHCV polymerase inhibitor and at least one NS5A inhibitor (e.g., acombination of at least one HCV NS5A inhibitor and at least onenon-nucleoside or nucleotide polymerase inhibitor, or a combination ofat least one HCV NS5A inhibitor and at least one nucleoside ornucleotide polymerase inhibitor, or a combination of at least one HCVNS5A inhibitor, at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside or nucleotide polymeraseinhibitor). In one example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 2 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 3 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the combination of two or more DAAs includes PSI-7977, Compound1 (with ritonavir), and Compound 4. In still another example, the methodcomprises administering to a patient in need thereof an effective amountof PSI-7977 as the sole DAA in lieu of a combination of two or moreDAAs, together with an effective amount of ribavirin. In still anotherexample, the method comprises administering 100 or 200 mg Compound 1together with 100 mg ritonavir once daily, and 25 mg compound 4 oncedaily. In yet another example, the method comprises administering 150 mgor 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400mg Compound 2 twice daily. In another example, the method comprisesadministering 150 mg Compound 1 together with 100 mg ritonavir oncedaily, and 400 mg Compound 3 once daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 twice daily. In another example, themethod comprises administering 100 or 150 mg Compound 1 together with100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mgCompound 2 twice daily. In another example, the method comprisesadministering 100 or 150 mg Compound 1 together with 100 mg ritonavironce daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twicedaily. Ribavirin can be administered based on patient weight, and inmany cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can alsobe included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 5 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside ornucleotide polymerase inhibitor, or a combination of at least one HCVNS5A inhibitor and at least one nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor, at leastone nucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor). In one example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 2 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In another example, the combination of twoor more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 3 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In still another example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof)and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) canbe co-formulated with ritonavir. In a further example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof),Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).Compound 1 (or a salt thereof) can be co-formulated with ritonavir. Inyet another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof), Compound 3 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs comprises PSI-7977 and PSI-938. Inyet another example, the combination of two or more DAAs comprisesPSI-7977 and TMC-435. In yet another example, the combination of two ormore DAAs comprises BMS-790052 and BMS-650032. In yet another example,the combination of two or more DAAs comprises GS-5885, GS-9190, andGS-9451. In yet another example, the combination of two or more DAAscomprises BI-201335 and BI-207127. In yet another example, thecombination of two or more DAAs comprises telaprevir and VX-222. Inanother example, the combination of two or more DAAs comprises GS-5885and GS-9451. In yet another example, the combination of two or more DAAsincludes danoprevir (with ritonavir) and R7128. In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-790052. Inyet another example, the combination of two or more DAAs includesPSI-7977 and BMS-650032 (asunaprevir). In still another example, thecombination of two or more DAAs includes PSI-7977, BMS-650032(asunaprevir) and BMS-790052 (daclatasvir). In yet another example, thecombination of two or more DAAs includes INX-189 and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-650032 (asunaprevir). In still anotherexample, the combination of two or more DAAs includes INX-189,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still anotherexample, the combination of two or more DAAs includes mericitabine anddanoprevir. In still another example, the combination of two or moreDAAs includes INX-189, daclatasvir and BMS-791325. In still anotherexample, the combination of two or more DAAs includes PSI-7977 andGS-5885. In still another example, the method comprises administering toa patient in need thereof an effective amount of PSI-7977 as the soleDAA in lieu of a combination of two or more DAAs, together with aneffective amount of ribavirin. In still another example, the methodcomprises administering 100 or 200 mg Compound 1 together with 100 mgritonavir once daily, and 25 mg compound 4 once daily. In yet anotherexample, the method comprises administering 150 mg or 250 mg Compound 1together with 100 mg ritonavir once daily, and 400 mg Compound 2 twicedaily. In another example, the method comprises administering 150 mgCompound 1 together with 100 mg ritonavir once daily, and 400 mgCompound 3 once daily. In another example, the method comprisesadministering 150 mg Compound 1 together with 100 mg ritonavir oncedaily, and 400 mg Compound 3 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2twice daily. In another example, the method comprises administering 100or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mgcompound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin canbe administered based on patient weight, and in many cases, 1000 to 1200mg divided twice daily. Other DAA(s) can also be included in a treatmentregimen according to this aspect of the technology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 4 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside or nucleotide polymeraseinhibitors, or a combination of at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least two non-nucleoside polymeraseinhibitors). For another instance, the combination of two or more DAAscan be a combination of at least two HCV protease inhibitors. Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV NS5A inhibitors. For another instance,the combination of two or more DAAs can be a combination of at least oneHCV polymerase inhibitor and at least one NS5A inhibitor (e.g., acombination of at least one HCV NS5A inhibitor and at least onenon-nucleoside polymerase inhibitor, or a combination of at least oneHCV NS5A inhibitor and at least one nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor, at leastone nucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor). In one example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 2 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In another example, the combination of twoor more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 3 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In still another example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof)and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) canbe co-formulated with ritonavir. In a further example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof),Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).Compound 1 (or a salt thereof) can be co-formulated with ritonavir. Inyet another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof), Compound 3 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs comprises PSI-7977 and PSI-938. Inyet another example, the combination of two or more DAAs comprisesPSI-7977 and TMC-435. In yet another example, the combination of two ormore DAAs comprises BMS-790052 and BMS-650032. In yet another example,the combination of two or more DAAs comprises GS-5885, GS-9190, andGS-9451. In yet another example, the combination of two or more DAAscomprises BI-201335 and BI-207127. In yet another example, thecombination of two or more DAAs comprises telaprevir and VX-222. Inanother example, the combination of two or more DAAs comprises GS-5885and GS-9451. In yet another example, the combination of two or more DAAsincludes danoprevir (with ritonavir) and R7128. In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-790052. Inyet another example, the combination of two or more DAAs includesPSI-7977 and BMS-650032 (asunaprevir). In still another example, thecombination of two or more DAAs includes PSI-7977, BMS-650032(asunaprevir) and BMS-790052 (daclatasvir). In yet another example, thecombination of two or more DAAs includes INX-189 and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-650032 (asunaprevir). In still anotherexample, the combination of two or more DAAs includes INX-189,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still anotherexample, the combination of two or more DAAs includes mericitabine anddanoprevir. In still another example, the combination of two or moreDAAs includes INX-189, daclatasvir and BMS-791325. In still anotherexample, the combination of two or more DAAs includes PSI-7977 andGS-5885. In still another example, the method comprises administering toa patient in need thereof an effective amount of PSI-7977 as the soleDAA in lieu of a combination of two or more DAAs, together with aneffective amount of ribavirin. In still another example, the methodcomprises administering 100 or 200 mg Compound 1 together with 100 mgritonavir once daily, and 25 mg compound 4 once daily. In yet anotherexample, the method comprises administering 150 mg or 250 mg Compound 1together with 100 mg ritonavir once daily, and 400 mg Compound 2 twicedaily. In another example, the method comprises administering 150 mgCompound 1 together with 100 mg ritonavir once daily, and 400 mgCompound 3 once daily. In another example, the method comprisesadministering 150 mg Compound 1 together with 100 mg ritonavir oncedaily, and 400 mg Compound 3 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2twice daily. In another example, the method comprises administering 100or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mgcompound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin canbe administered based on patient weight, and in many cases, 1000 to 1200mg divided twice daily. Other DAA(s) can also be included in a treatmentregimen according to this aspect of the technology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 3 weeks (or evenless, depending on the patient's condition) and does not includeadministration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor and atleast one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor, at least one nucleosideor nucleotide polymerase inhibitor and at least one non-nucleosidepolymerase inhibitor). In one example, the combination of two or moreDAAs is a combination of Compound 1 (or a salt thereof) and Compound 2(or a salt thereof). Compound 1 (or a salt thereof) can be co-formulatedwith ritonavir. In another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 3 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 24 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside ornucleotide polymerase inhibitor, or a combination of at least one HCVNS5A inhibitor and at least one nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor, at leastone nucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor). In one example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 2 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir.

In another example, the combination of two or more DAAs is a combinationof Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof).Compound 1 (or a salt thereof) can be co-formulated with ritonavir. Instill another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts from 13 to 23 weeks(e.g., the duration of the treatment is selected from 13, 14, 15, 16,17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administrationof any interferon. The DAAs and ribavirin can be administered at thesame or different dosing frequency. The patient being treated can be atreatment naïve patient, a treatment experienced patient, including, butnot limited to, a relapser, an interferon partial responder, aninterferon non-responder (e.g., a null responder), or a patient unableto take interferon. The patient can be infected with, for example andwithout limitation, HCV genotype 1, such as HCV genotype 1a or HCVgenotype 1b; or HCV genotype 2 or 3. The treatment according to thisaspect of the technology can also be effective against other HCVgenotypes. The DAAs can be administered around the same time or atdifferent times, and can be co-formulated in a single formulation orformulated in different compositions. Each DAA can be selected from HCVprotease inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors.For instance, the combination of two or more DAAs can be a combinationof at least one HCV protease inhibitor and at least one HCV polymeraseinhibitor (e.g., a combination of at least one HCV protease inhibitorand at least one non-nucleoside polymerase inhibitor, or a combinationof at least one HCV protease inhibitor and at least one nucleoside ornucleotide polymerase inhibitor, or a combination of at least one HCVprotease inhibitor, at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside inhibitor). For anotherinstance, the combination of two or more DAAs can be a combination of atleast one HCV protease inhibitor and at least one HCV NS5A inhibitor.For still another instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor, at least one HCVpolymerase inhibitor, and at least one HCV NS5A inhibitor. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV polymerase inhibitors (e.g., a combination of at least twonucleoside polymerase inhibitors, or a combination of at least onenucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor, or a combination of at least twonon-nucleoside polymerase inhibitors). For another instance, thecombination of two or more DAAs can be a combination of at least two HCVprotease inhibitors. For another instance, the combination of two ormore DAAs can be a combination of at least two HCV NS5A inhibitors. Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV polymerase inhibitor and at least oneNS5A inhibitor (e.g., a combination of at least one HCV NS5A inhibitorand at least one non-nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV NS5A inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside polymeraseinhibitor). In one example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 2 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 3 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 12 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor and atleast one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor, at least one nucleosideor nucleotide polymerase inhibitor and at least one non-nucleosideinhibitor). In one example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 2 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof) and Compound 3 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052 (daclatasvir). In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 11 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor and atleast one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor, at least one nucleosideor nucleotide polymerase inhibitor and at least one non-nucleosidepolymerase inhibitor). In one example, the combination of two or moreDAAs is a combination of Compound 1 (or a salt thereof) and Compound 2(or a salt thereof). Compound 1 (or a salt thereof) can be co-formulatedwith ritonavir. In another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 3 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 10 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be a treatment naïve patient, a treatment experiencedpatient, including, but not limited to, a relapser, an interferonpartial responder, an interferon non-responder (e.g., a null responder),or a patient unable to take interferon. The patient can be infectedwith, for example and without limitation, HCV genotype 1, such as HCVgenotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The DAAs can be administered around the same timeor at different times, and can be co-formulated in a single formulationor formulated in different compositions. Each DAA can be selected fromHCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5Ainhibitors. For instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVpolymerase inhibitor (e.g., a combination of at least one HCV proteaseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least one HCV protease inhibitor and at least onenucleoside or nucleotide polymerase inhibitor, or a combination of atleast one HCV protease inhibitor, at least one nucleoside or nucleotidepolymerase inhibitor and at least one non-nucleoside inhibitor). Foranother instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. For still another instance, the combination of two ormore DAAs can be a combination of at least one HCV protease inhibitor,at least one HCV polymerase inhibitor, and at least one HCV NS5Ainhibitor. For another instance, the combination of two or more DAAs canbe a combination of at least two HCV polymerase inhibitors (e.g., acombination of at least two nucleoside polymerase inhibitors, or acombination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside polymerase inhibitor, or acombination of at least two non-nucleoside polymerase inhibitors). Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV protease inhibitors. For anotherinstance, the combination of two or more DAAs can be a combination of atleast two HCV NS5A inhibitors. For another instance, the combination oftwo or more DAAs can be a combination of at least one HCV polymeraseinhibitor and at least one NS5A inhibitor (e.g., a combination of atleast one HCV NS5A inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor and atleast one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV NS5A inhibitor, at least one nucleosideor nucleotide polymerase inhibitor and at least one non-nucleosidepolymerase inhibitor). In one example, the combination of two or moreDAAs is a combination of Compound 1 (or a salt thereof) and Compound 2(or a salt thereof). Compound 1 (or a salt thereof) can be co-formulatedwith ritonavir. In another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 3 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In still another example, the combination of two or more DAAsis a combination of Compound 1 (or a salt thereof) and Compound 4 (or asalt thereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In a further example, the combination of two or more DAAs isa combination of Compound 1 (or a salt thereof), Compound 2 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs is a combination of Compound 1 (or asalt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a saltthereof). Compound 1 (or a salt thereof) can be co-formulated withritonavir. In yet another example, the combination of two or more DAAscomprises PSI-7977 and PSI-938. In yet another example, the combinationof two or more DAAs comprises PSI-7977 and TMC-435. In yet anotherexample, the combination of two or more DAAs comprises BMS-790052 andBMS-650032. In yet another example, the combination of two or more DAAscomprises GS-5885, GS-9190, and GS-9451. In yet another example, thecombination of two or more DAAs comprises BI-201335 and BI-207127. Inyet another example, the combination of two or more DAAs comprisestelaprevir and VX-222. In another example, the combination of two ormore DAAs comprises GS-5885 and GS-9451. In yet another example, thecombination of two or more DAAs includes danoprevir (with ritonavir) andR7128. In yet another example, the combination of two or more DAAsincludes PSI-7977 and BMS-790052. In yet another example, thecombination of two or more DAAs includes PSI-7977 and BMS-650032(asunaprevir). In still another example, the combination of two or moreDAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-790052 (daclatasvir). In yet anotherexample, the combination of two or more DAAs includes INX-189 andBMS-650032 (asunaprevir). In still another example, the combination oftwo or more DAAs includes INX-189, BMS-650032 (asunaprevir) andBMS-790052 (daclatasvir). In still another example, the combination oftwo or more DAAs includes mericitabine and danoprevir. In still anotherexample, the combination of two or more DAAs includes INX-189,daclatasvir and BMS-791325. In still another example, the combination oftwo or more DAAs includes PSI-7977 and GS-5885. In still anotherexample, the method comprises administering to a patient in need thereofan effective amount of PSI-7977 as the sole DAA in lieu of a combinationof two or more DAAs, together with an effective amount of ribavirin. Instill another example, the method comprises administering 100 or 200 mgCompound 1 together with 100 mg ritonavir once daily, and 25 mg compound4 once daily. In yet another example, the method comprises administering150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 150 mg Compound 1 together with 100 mg ritonavironce daily, and 400 mg Compound 3 once daily. In another example, themethod comprises administering 150 mg Compound 1 together with 100 mgritonavir once daily, and 400 mg Compound 3 twice daily. In anotherexample, the method comprises administering 100 or 150 mg Compound 1together with 100 mg ritonavir once daily, 25 mg compound 4 once daily,and 400 mg Compound 2 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3twice daily. Ribavirin can be administered based on patient weight, andin many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) canalso be included in a treatment regimen according to this aspect of thetechnology.

In yet another aspect, the present technology features a method oftreating HCV, comprising administering to a patient in need thereof aneffective amount of a combination of two or more DAAs, together with aneffective amount of ribavirin. The treatment lasts 9 weeks and does notinclude administration of any interferon. The DAAs and ribavirin can beadministered at the same or different dosing frequency. The patientbeing treated can be an interferon naïve patient, a treatmentexperienced patient, including, but not limited to, a relapser, aninterferon partial responder, an interferon non-responder (e.g., a nullresponder), or a patient unable to take interferon. The patient can beinfected with, for example and without limitation, HCV genotype 1, suchas HCV genotype 1a or HCV genotype 1b; or HCV genotype 2 or 3. Thetreatment according to this aspect of the technology can also beeffective against other HCV genotypes. The DAAs can be administeredaround the same time or at different times, and can be co-formulated ina single formulation or formulated in different compositions. Each DAAcan be selected from HCV protease inhibitors, HCV polymerase inhibitors,or HCV NS5A inhibitors. For instance, the combination of two or moreDAAs can be a combination of at least one HCV protease inhibitor and atleast one HCV polymerase inhibitor (e.g., a combination of at least oneHCV protease inhibitor and at least one non-nucleoside polymeraseinhibitor, or a combination of at least one HCV protease inhibitor andat least one nucleoside or nucleotide polymerase inhibitor, or acombination of at least one HCV protease inhibitor, at least onenucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside inhibitor). For another instance, the combination of twoor more DAAs can be a combination of at least one HCV protease inhibitorand at least one HCV NS5A inhibitor. For still another instance, thecombination of two or more DAAs can be a combination of at least one HCVprotease inhibitor, at least one HCV polymerase inhibitor, and at leastone HCV NS5A inhibitor. For another instance, the combination of two ormore DAAs can be a combination of at least two HCV polymerase inhibitors(e.g., a combination of at least two nucleoside polymerase inhibitors,or a combination of at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside or nucleotide polymeraseinhibitor, or a combination of at least two non-nucleoside polymeraseinhibitors). For another instance, the combination of two or more DAAscan be a combination of at least two HCV protease inhibitors. Foranother instance, the combination of two or more DAAs can be acombination of at least two HCV NS5A inhibitors. For another instance,the combination of two or more DAAs can be a combination of at least oneHCV polymerase inhibitor and at least one NS5A inhibitor (e.g., acombination of at least one HCV NS5A inhibitor and at least onenon-nucleoside polymerase inhibitor, or a combination of at least oneHCV NS5A inhibitor and at least one nucleoside or nucleotide polymeraseinhibitor, or a combination of at least one HCV NS5A inhibitor, at leastone nucleoside or nucleotide polymerase inhibitor and at least onenon-nucleoside polymerase inhibitor). In one example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 2 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In another example, the combination of twoor more DAAs is a combination of Compound 1 (or a salt thereof) andCompound 3 (or a salt thereof). Compound 1 (or a salt thereof) can beco-formulated with ritonavir. In still another example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof)and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) canbe co-formulated with ritonavir. In a further example, the combinationof two or more DAAs is a combination of Compound 1 (or a salt thereof),Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).Compound 1 (or a salt thereof) can be co-formulated with ritonavir. Inyet another example, the combination of two or more DAAs is acombination of Compound 1 (or a salt thereof), Compound 3 (or a saltthereof) and Compound 4 (or a salt thereof). Compound 1 (or a saltthereof) can be co-formulated with ritonavir. In yet another example,the combination of two or more DAAs comprises PSI-7977 and PSI-938. Inyet another example, the combination of two or more DAAs comprisesPSI-7977 and TMC-435. In yet another example, the combination of two ormore DAAs comprises BMS-790052 and BMS-650032. In yet another example,the combination of two or more DAAs comprises GS-5885, GS-9190, andGS-9451. In yet another example, the combination of two or more DAAscomprises BI-201335 and BI-207127. In yet another example, thecombination of two or more DAAs comprises telaprevir and VX-222. Inanother example, the combination of two or more DAAs comprises GS-5885and GS-9451. In yet another example, the combination of two or more DAAsincludes danoprevir (with ritonavir) and R7128. In yet another example,the combination of two or more DAAs includes PSI-7977 and BMS-790052. Inyet another example, the combination of two or more DAAs includesPSI-7977 and BMS-650032 (asunaprevir). In still another example, thecombination of two or more DAAs includes PSI-7977, BMS-650032(asunaprevir) and BMS-790052 (daclatasvir). In yet another example, thecombination of two or more DAAs includes INX-189 and BMS-790052(daclatasvir). In yet another example, the combination of two or moreDAAs includes INX-189 and BMS-650032 (asunaprevir). In still anotherexample, the combination of two or more DAAs includes INX-189,BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still anotherexample, the combination of two or more DAAs includes mericitabine anddanoprevir. In still another example, the combination of two or moreDAAs includes INX-189, daclatasvir and BMS-791325. In still anotherexample, the combination of two or more DAAs includes PSI-7977 andGS-5885. In still another example, the method comprises administering toa patient in need thereof an effective amount of PSI-7977 as the soleDAA in lieu of a combination of two or more DAAs, together with aneffective amount of ribavirin. In still another example, the methodcomprises administering 100 or 200 mg Compound 1 together with 100 mgritonavir once daily, and 25 mg compound 4 once daily. In yet anotherexample, the method comprises administering 150 mg or 250 mg Compound 1together with 100 mg ritonavir once daily, and 400 mg Compound 2 twicedaily. In another example, the method comprises administering 150 mgCompound 1 together with 100 mg ritonavir once daily, and 400 mgCompound 3 once daily. In another example, the method comprisesadministering 150 mg Compound 1 together with 100 mg ritonavir oncedaily, and 400 mg Compound 3 twice daily. In another example, the methodcomprises administering 100 or 150 mg Compound 1 together with 100 mgritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2twice daily. In another example, the method comprises administering 100or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mgcompound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin canbe administered based on patient weight, and in many cases, 1000 to 1200mg divided twice daily. Other DAA(s) can also be included in a treatmentregimen according to this aspect of the technology.

In another embodiment, the present technology provides interferon-freetreatment comprising administering daily two DAAs with ribavirin, wherethe two DAAs include a HCV polymerase inhibitor, for example PSI-7977and a NS5A inhibitor, for example BMS-790052 for a duration of no morethan twelve weeks (e.g., no more than eleven weeks), preferably no morethan eight weeks.

In some embodiments, the present technology provides a method oftreating Hepatitis C virus infection in a subject comprisingadministering daily a HCV protease inhibitor and a HCV polymeraseinhibitor to the subject in the absence of interferon for a duration ofno more than twelve weeks, preferably no more than eight weeks. In someembodiments, ritonavir (or an equivalent thereof) is co-administeredwith one or more protease inhibitors to improve the pharmacokinetics ofthe protease inhibitor(s). The treatment further comprises administeringribavirin to the patient. In some embodiments, the HCV polymeraseinhibitor is at least one nucleoside or nucleotide polymerase inhibitoror at least one non-nucleoside polymerase inhibitor. In someembodiments, both a nucleoside or nucleotide polymerase inhibitors and anon-nucleoside polymerase inhibitor may be administered.

The methods of the present technology as described herein may be used totreat a naïve patient or a treatment experienced patient. Treatmentexperienced patients include interferon non-responders, partialresponders (patients whose HCV RNA levels declined but never becameundetectable), and relapsers (patients who achieved undetectable levelsof HCV RNA during therapy but rebound). Methods of the presenttechnology may also be used to treat patients who are not candidates forinterferon treatment. Patients who are not candidates for interferontreatment include, but are not limited to, one or more of the followinggroups: patients intolerant to interferon, patients who refuse to takeinterferon treatment, patients with medical conditions which precludethem from taking interferon, and patients who have an increased risk ofside effects or infection by taking interferon.

In some embodiments, a cytochrome P-450 inhibitor, e.g. ritonavir, isadministered either in the same or separate pharmaceutical compositionwith the protease inhibitor (e.g. Compound 1 (or a pharmaceuticallyacceptable salt thereof)) to improve the pharmacokinetics. A cytochromeP450 inhibitor reduces the metabolism of some protease inhibitors, suchas Compound 1, thereby improving the pharmacokinetics andbioavailability of the protease inhibitor, for example Compound 1. Morepreferably, Compound 1 (or a pharmaceutically acceptable salt thereof)is co-formulated with ritonavir in the same dosage form. Othercytochrome P450 inhibitors, such as cobicistat, may also be administeredin lieu of ritonavir, to enhance the pharmacokinetics of Compound 1 (ora pharmaceutically acceptable salt thereof).

Inhibitors of cytochrome P450, such as ritonavir, may be co-administeredwith the DAAs, either sequentially or simultaneously, in the same ordifferent compositions. In some embodiments, the cytochrome P450inhibitors are administered in order to improve the pharmacokinetics ofat least one of the DAAs. Not to be bound by any theory, but acytochrome P450 inhibitor may also reduce the development of resistantstrains of HCV when co-administered with a DAA, thus providing theeffectiveness in a shorter treatment. In some embodiments, ritonavir isco-administered with therapeutic agent 1. In some embodiments, ritonaviris co-administered with therapeutic agent 1 in the same compositions.

In some embodiments, the present technology provides a method oftreating HCV infection comprising administering at least one proteaseinhibitor and at least one HCV polymerase inhibitor with ribavirin in acourse of treatment of no more than, or less than, eight weeks in theabsence of interferon. In some embodiments, the HCV polymerase inhibitoris Compound 1 (or a pharmaceutically acceptable salt thereof).

In some embodiments, the present technology provides a method oftreating HCV infection without using interferon, the method comprisingadministering at least two DAAs and ribavirin to a patient in need ofsuch treatment, wherein the at least two DAAs include at least oneprotease inhibitor and at least one HCV polymerase inhibitor. In someembodiments, the at least two DAAs includes therapeutic agent 1 with atleast one HCV polymerase inhibitor. In some embodiments, the HCVpolymerase inhibitor is at least one non-nucleoside polymeraseinhibitor. In some embodiments, the non-nucleoside polymerase inhibitoris therapeutic agent 2 or therapeutic agent 3 or a combination thereof.

In some embodiments, the present technology provides a method oftreating HCV infection without using interferon, the method comprisingadministering a HCV protease inhibitor, preferably therapeutic agent 1,with at least one HCV NS5A inhibitor to a patient in need of suchtreatment. In some embodiments, the NS5A inhibitor is therapeutic agent4.

In some embodiments of the present technology, a method of treating HCVinfection without using interferon, the method comprises administeringat least three DAAs and ribavirin to a subject for no more than 8 weekswithout administering interferon. The at least three DAAs can be atleast one protease inhibitor, at least one HCV polymerase inhibitor, andat least one NS5A inhibitors. In a preferred embodiment, the at leastone protease inhibitor is therapeutic agent 1, the at least onepolymerase inhibitor is therapeutic agent 2 or therapeutic agent 3, andthe at least one NS5A inhibitor is therapeutic agent 4.

Preferred HCV protease inhibitors include, but are not limited to,therapeutic agent 1, telaprevir (Vertex), boceprevir (Merck), BI-201335(Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Othersuitable protease inhibitors include, but are not limited to, ACH-1095(Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181(Avila), AVL-192 (Avila), BMS-650032 (BMS), danoprevir (RG7227/ITMN-191,Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX-136 (Idenix), IDX-316(Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir(Schering-Plough Corp), PHX-1766 (Phenomix), TMC-435 (Tibotec),vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-500 (Vertex), VX-813(Vertex), VX-985 (Vertex), or a combination thereof.

Preferred non-nucleoside HCV polymerase inhibitors for use in thepresent technology include, but are not limited to, therapeutic agent 2,therapeutic agent 3, GS-9190 (Gilead), BI-207127 (Boehringer Ingelheim),and VX-222 (VCH-222) (Vertex & ViraChem). Preferred nucleotide HCVpolymerase inhibitors include, but are not limited to, PSI-7977(Pharmasset), and PSI-938 (Pharmasset). Other suitable and non-limitingexamples of suitable HCV polymerase inhibitors include ANA-598 (Anadys),BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim),BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669(Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055(Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-759(Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189(Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912 (Medivir),GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ALS-2200 (AliosBioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combinationthereof. A polymerase inhibitor may be a nucleoside polymeraseinhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix),INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938(Pharmasset), RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (AliosBioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combinationtherefore. A polymerase inhibitor may also be a non-nucleosidepolymerase inhibitor, such as PF-00868554 (Pfizer), ANA-598 (Anadys),BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim),BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669(Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055(Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222(VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combinationthereof.

Preferred NS5A inhibitors include, but are not limited to, therapeuticagent 4, BMS-790052 (BMS) and GS-5885 (Gilead). Non-limiting examples ofsuitable NS5A inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928(Achillion), AZD2836 (Astra-Zeneca), AZD7295 (Astra-Zeneca), BMS-790052(BMS), BMS-824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461(Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or acombination thereof.

Non-limiting examples of suitable cyclophilin inhibitors includealisporovir (Novartis & Debiopharm), NM-811 (Novartis), SCY-635(Scynexis), or a combination thereof.

Non-limiting examples of suitable HCV entry inhibitors include ITX-4520(iTherx), ITX-5061 (iTherx), or a combination thereof.

Specific examples of other DAA agents that are suitable for the presentmethods include, but are not limited to, AP-H005, A-831 (ArrowTherapeutics) (NS5A inhibitor), A-689 (Arrow Therapeutics) (NS5Ainhibitor), INX08189 (Inhibitex) (polymerase inhibitor), ITMN-191(Intermune/Roche) (NS3/4A Protease inhibitor), VBY-376 (ProteaseInhibitor) (Virobay), ACH-1625 (Achillion, Protease inhibitor), IDX136(Idenix, Protease Inhibitor), IDX316 (Idenix, Protease inhibitor),VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 (Tibotec),ITMN-191 (Intermune, Roche), MK-7009 (Merck), IDX-PI (Novartis), R7128(Roche), PF-868554 (Pfizer) (non-nucleoside polymerase inhibitor),PF-4878691 (Pfizer), IDX-184 (Idenix), IDX-375 (Idenix, NS5B polymeraseinhibitor), PPI-461 (Presidio), BILB-1941 (Boehringer Ingelheim),GS-9190 (Gilead), BMS-790052 (BMS), CTS-1027 (Conatus), GS-9620(Gilead), PF-4878691 (Pfizer), R05303253 (Roche), ALS-2200 (AliosBioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), GSK62336805(GlaxoSmithKline), or any combinations thereof.

In some embodiments, the present technology features methods fortreating patients with genotype 1, such as 1a or 1b, HCV infection. Themethods comprise administering to such a patient a combination of atleast 2 DAAs and ribavirin for no more than 12 weeks, preferably no morethan 8 weeks, wherein the treatment does not include administration ofinterferon. Patients with genotype 1, such as 1a or 1b, infection can betreated with a combination of at least 2 DAAs without interferon wherethe at least two DAAs include therapeutic agent 1 and therapeutic agent2 with ribavirin. Therapeutic agent 1 and therapeutic agent 2 withribavirin can be administered in therapeutically effective amounts toprovide a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) after atreatment duration of no more than 12 weeks (e.g., the duration being 12weeks), preferably no more than 8 weeks (e.g., the duration being 8weeks). The patients may be treatment naïve patients or treatmentexperienced HCV patients. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan t 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks. The total daily dosage oftherapeutic agent 1 can be, but is not limited to, for example, about100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.Therapeutic agent 2 can be administered with therapeutic agent 1 in anyof the dosages of therapeutic agent 1 described above. The total dailydosage of therapeutic agent 2 can be, but is not limited to, forexample, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about800 mg, about 900 mg, about 1000 mg, about 1500 mg, or 1800 mg.Suitably, ribavirin may be administered in connection with therapeuticagent 1 and therapeutic agent 2 at any of the dosages described above.Suitable total daily dosages of ribavirin can be based on the weight ofthe patient and include, but are not limited to, from about 800 mg toabout 1200 mg, including, for example, about 1000 mg per day for apatient <75 kg or about 1200 mg per day for a patient ≧75 kg. In someembodiments, ritonavir can be either co-administered or administeredseparately with therapeutic agent 1. Suitable dosages of ritonavirinclude, but are not limited to, from about 50 mg to about 400 mg perday, preferably about 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with genotype 2 or 3 HCV infection. The methodscomprise administering to such a patient a combination of at least 2DAAs and ribavirin for no more than 12 weeks (e.g., the duration being12 weeks), preferably no more than 8 weeks (e.g., the duration being 8weeks), wherein the treatment does not include administration ofinterferon. Patients with genotype 2 or 3 HCV infection can be treatedwith a combination of at least 2 DAAs without interferon where the atleast two DAAs include therapeutic agent 1 and therapeutic agent 2 withribavirin. Therapeutic agent 1 and therapeutic agent 2 can beadministered in therapeutically effective amounts to provide a SVR (forexample, a SVR8, SVR12, SVR16, or SVR24) with a treatment duration of nomore than 12 weeks, preferably no more than 8 weeks. The patients may betreatment naïve HCV patients or treatment experienced HCV patients. Thetreatment duration can be no more than 12 weeks, including but notlimited to, no more than 11 weeks, no more than 10 weeks, no more than 9weeks, but preferably no more than 8 weeks, no more than 7 weeks, nomore than 6 weeks, no more than 5 weeks, no more than 4 weeks, or nomore than 3 weeks, e.g., the duration being 12 weeks, or the durationbeing 8 weeks. The total daily dosage of therapeutic agent 1 can be, butis not limited to, for example, about 100 mg, about 110 mg, about 120mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, about 300 mg. Therapeutic agent 2 can be administeredin connection with therapeutic agent 1 in any of the dosages describedabove. The total daily dosage of therapeutic agent 2 can be, but is notlimited to, about 400 mg, about 500 mg, about 600 mg, about 700 mg,about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or 1800 mg.Suitably, ribavirin may be administered in connection with therapeuticagent 1 and therapeutic agent 2 in any combination of suitable dosagesdescribed above. Suitable total daily dosages of ribavirin can be basedon the weight of the patient and include, but are not limited to, fromabout 800 mg to about 1200 mg, including, for example, about 1000 mg perday for a patient <75 kg or about 1200 mg per day for a patient ≧75 kg.In some embodiments, ritonavir can be either co-administered oradministered separately with therapeutic agent 1. Suitable dosages ofritonavir include, from about 50 mg to about 400 mg per day, preferablyabout 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with HCV infection. The methods comprise administeringto such a patient a combination of at least 2 DAAs and ribavirin for nomore than 12 weeks (e.g., the duration being 12 weeks), preferably nomore than 8 weeks (e.g., the duration being 8 weeks), wherein thetreatment does not include administration of interferon. The combinationcomprises therapeutic agent 1, therapeutic agent 2 and ribavirin.Suitably, the patient may be a treatment naïve patient, a treatmentexperienced patient or an interferon nonresponder. In some embodiments,the patient is infected with HCV genotype 1, such as genotype 1a. Insome embodiments, the patient is infected with HCV genotype 1b. In someembodiments, the patient is infected with HCV genotype 2 or 3, such as2a or 2b. In some other embodiments, the patient is infected with HCVgenotype 3a. The treatment according to this aspect of the technologycan also be effective against other HCV genotypes. The treatmentduration can be for no more than 12 weeks, preferably no more than 8weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks. Therapeutic agent 1 andtherapeutic agent 2 can be administered in therapeutically effectiveamounts to provide a SVR (for example, a SVR8, SVR12, SVR 16, or SVR 24)after treatment duration of no more than 12 weeks, preferably no morethan 8 weeks. The total daily dosage of therapeutic agent 1 can be, butis not limited to, for example, about 100 mg, about 110 mg, about 120mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, or about 300 mg. Therapeutic agent 2 can beadministered with therapeutic agent 1 in any of the dosages describedabove. The total daily dosage of therapeutic agent 2 can be, but is notlimited to, for example, about 400 mg, about 500 mg, about 600 mg, about700 mg, about 800 mg, about 900 mg, about 1000 mg. Suitably, ribavirinmay be administered in connection with therapeutic agent 1 andtherapeutic agent 2 at any combination of the dosages described above.Suitable total daily dosages of ribavirin can be based on the weight ofthe patient and include, but are not limited to, from about 800 mg toabout 1200 mg, including, for example, about 1000 mg per day for apatient <75 kg or about 1200 mg per day for a patient ≧75 kg.

In some embodiments, the present technology features methods fortreating patients with HCV infection who are not candidates forinterferon treatment. The methods comprise administering to such apatient a combination of at least 2 DAAs and ribavirin for no more than12 weeks (e.g., the duration being 12 weeks), preferably no more than 8weeks (e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. Patients who are not candidatesfor interferon treatment include, but are not limited to, one or more ofthe following groups: patients intolerant to interferon, patients whorefuse to take interferon treatment, patients with medical conditionswhich preclude them from taking interferon, and patients who have anincreased risk of side effects or infection by taking interferon. Anon-candidate for interferon treatment can be infected with HCV genotype1 or 2, for example, genotype 1a or 1b. A non-candidate for interferontreatment can be infected with HCV genotype 2, for example, genotype 2aor 2b. The treatment according to this aspect of the technology can alsobe effective against other HCV genotypes. In some embodiments,non-candidate for interferon treatment patients can be treated with acombination of at least 2 DAAs without interferon and with ribavirin fora treatment duration of no more than 12 weeks, including but not limitedto, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks,but preferably no more than 8 weeks, no more than 7 weeks, no more than6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.The at least two DAAs include at least one HCV protease inhibitor and atleast one HCV polymerase inhibitor. Suitably, the at least one HCVprotease inhibitor can be therapeutic agent 1 and the at least one HCVpolymerase inhibitor can be therapeutic agent 2. Therapeutic agent 1 andtherapeutic agent 2 can be administered in therapeutically effectiveamounts to provide a SVR after a treatment duration of no more than 12weeks, preferably no more than 8 weeks. The total daily dosage oftherapeutic agent 1 can be, but is not limited to, for example, about100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.Therapeutic agent 2 can be administered with therapeutic agent 1 withtherapeutic agent 1 administered at any of the dosages described above.The total daily dosage of therapeutic agent 2 can be, but is not limitedto, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg,about 800 mg, about 900 mg, or about 1000 mg. Suitably, ribavirin may beadministered in connection with therapeutic agent 1 and therapeuticagent 2 at any of the dosages described above. Suitable total dailydosages of ribavirin can be based on the weight of the patient andinclude, but are not limited to, from about 800 mg to about 1200 mg,including, for example, about 1000 mg per day for a patient <75 kg orabout 1200 mg per day for a patient ≧75 kg.

In another aspect, the present technology features methods for treatingpatients with HCV infection. The methods comprise administering to sucha patient a combination of at least 2 DAAs and ribavirin for no morethan 12 weeks (e.g., the duration being 12 weeks), preferably no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 2, therapeutic agent 4 andribavirin. In some embodiments, the patient is infected with HCVgenotype 1, such as genotype 1a. The treatment according to this aspectof the technology can also be effective against other HCV genotypes. Thetreatment duration can be no more than 12 weeks, including but notlimited to, no more than 11 weeks, no more than 10 weeks, no more than 9weeks, but preferably no more than 8 weeks, no more than 7 weeks, nomore than 6 weeks, no more than 5 weeks, no more than 4 weeks, or nomore than 3 weeks, e.g., the duration being 12 weeks or the durationbeing 8 weeks. Therapeutic agent 1, therapeutic agent 2, and therapeuticagent 3 can be provided in effective amounts to provide a SVR (forexample, a SVR8, SVR12, SVR16, or SVR24) after a treatment duration ofno more than 12 weeks, preferably no more than 8 weeks. The total dailydosage of therapeutic agent 1 can be, but is not limited to, forexample, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about300 mg. Therapeutic agent 2 can be administered with therapeutic agent 1with therapeutic agent 1 being administered in any of the dosagesdescribed above. The total daily dosage of therapeutic agent 2 can be,but is not limited to, for example, about 400 mg, about 500 mg, about600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.Therapeutic agent 4 can be provided in combination with therapeuticagent 1 and therapeutic agent 2 in which therapeutic agent 1 andtherapeutic agent 2 are administered in any combination of the dosagesfor therapeutic agent 1 and therapeutic agent 2 described above.Therapeutic agent 4 can be provided in combination with therapeuticagent 1 and therapeutic agent 2 in a total daily dose of therapeuticagent 4 of an amount from about 5 mg to about 350 mg, preferably about 5mg to about 300 mg, more preferably about 25 mg to about 200 mg. Thetotal daily dosage of therapeutic agent 4 can be, but are not limitedto, for example, about 20 mg, about 25 mg, about 30 mg, about 40 mg,about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about90 mg, or about 100 mg. In some embodiments, ritonavir can be eitherco-administered or administered separately with therapeutic agent 1.Suitable dosages of ritonavir include, from about 50 mg to about 400 mgper day, preferably about 100 mg per day. Suitably, ribavirin may beadministered in connection with therapeutic agent 1, therapeutic agent2, and therapeutic agent 4 in which therapeutic agent 1, therapeuticagent 2, and therapeutic agent 4 are administered in any combination ofthe dosages described above. Suitable total daily dosages of ribavirincan be based on the weight of the patient and include, but are notlimited to, from about 800 mg to about 1200 mg, including, for example,about 1000 mg per day for a patient <75 kg or about 1200 mg per day fora patient ≧75 kg. Suitably, in some embodiments, the patient may be atreatment naïve patient, a treatment experienced patient, or aninterferon nonresponder.

In some embodiments, the present technology features methods fortreating patients with genotype 1, such as genotype 1a or 1b, HCVinfection. The methods comprise administering to such a patient acombination of at least 2 DAAs and ribavirin for no more than 12 weeks(e.g., the duration being 12 weeks), preferably no more than 8 weeks(e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 3 and ribavirin. The treatmentduration may be no more than 12 weeks, including but not limited to, nomore than 11 weeks, no more than 10 weeks, no more than 9 weeks, butpreferably no more than 8 weeks, no more than 7 weeks, no more than 6weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.The total daily dosage of therapeutic agent 1 can be, but is not limitedto, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg,about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg,about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg,about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, orabout 300 mg. Therapeutic agent 3 can be administered in connection withtherapeutic agent 1 with therapeutic agent 1 being administered at anyof the dosages of described above. Therapeutic agent 3 can be providedin combination with therapeutic agent 1. The total daily dosage oftherapeutic agent 3 can be, but is not limited to, for example, about400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about950 mg, or about 1000 mg. Ribavirin can be administered either at thesame time or at a separate time than therapeutic agent 1 and therapeuticagent 3; and therapeutic agent 1 and therapeutic agent 3 can beadministered in any of the suitable dosages of therapeutic agent 1 ortherapeutic agent 3 recited above. Suitable total daily dosages ofribavirin can be based on the weight of the patient and include, but arenot limited to, from about 800 mg to about 1200 mg, including, forexample, about 1000 mg per day for a patient <75 kg or about 1200 mg perday for a patient ≧75 kg. In some embodiments, ritonavir can be eitherco-administered or administered separately with therapeutic agent 1.Suitable dosages of ritonavir include, from about 50 mg to about 400 mgper day, preferably about 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with genotype 2 or 3, such as genotype 2a, 2b or 3a,HCV infection. The methods comprise administering to such a patient acombination of at least 2 DAAs and ribavirin for no more than 12 weeks(e.g., the duration being 12 weeks), preferably no more than 8 weeks(e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 3 and ribavirin. The treatmentduration can be no more than 12 weeks, including but not limited to, nomore than 11 weeks, no more than 10 weeks, no more than 9 weeks, butpreferably no more than 8 weeks, no more than 7 weeks, no more than 6weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.Therapeutic agent 1 and therapeutic agent 3 and ribavirin can beadministered in therapeutically effective amounts to provide a SVR (forexample, a SVR8, SVR12, SVR16 or SVR24) in a treatment duration of nomore than 12 weeks, preferably no more than 8 weeks. The total dailydosage of therapeutic agent 1 can be, but is not limited to, forexample, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about300 mg. Therapeutic agent 3 can be administered with therapeutic agent 1with therapeutic agent 1 being administered at any of the dosagesdescribed above. Therapeutic agent 3 can be provided in combination withtherapeutic agent 1. The total daily dosage of therapeutic agent 3 canbe, but is not limited to, for example, about 300 mg, about 310 mg,about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg,about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg,about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg,about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg,about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg,about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg,about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg,about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000mg. Ribavirin can be administered either at the same time or at aseparate time than therapeutic agent 1 and therapeutic agent 3; andtherapeutic agent 1 and therapeutic agent 3 can be administered in anycombination of dosage of therapeutic agent 1 or therapeutic agent 3recited above. Suitable total daily dosages of ribavirin can be based onthe weight of the patient and include, but are not limited to, fromabout 800 mg to about 1200 mg, including, for example, about 1000 mg perday for a patient <75 kg or about 1200 mg per day for a patient ≧75 kg.In some embodiments, ritonavir can be either co-administered oradministered separately with therapeutic agent 1. Suitable dosages ofritonavir include, from about 50 mg to about 400 mg per day, preferablyabout 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with HCV infection. The methods comprise administeringto such a patient a combination of at least 2 DAAs and ribavirin for nomore than 12 weeks (e.g., the duration being 12 weeks), preferably nomore than 8 weeks (e.g., the duration being 8 weeks), wherein thetreatment does not include administration of interferon. The combinationcomprises therapeutic agent 1, therapeutic agent 3 and ribavirin.Suitably, the patient may be a treatment naïve patient, a treatmentexperienced patient or an interferon nonresponder. In some embodiments,the patient is infected with HCV genotype 1, such as genotype 1a. Insome embodiments, the patient is infected with HCV genotype 1b. In someother embodiments, the patient is infected with HCV genotype 2 or 3,such as 2a or 2b. In some other embodiments, the patient is infectedwith HCV genotype 3a. The treatment according to this aspect of thetechnology can also be effective against other HCV genotypes. Thetreatment duration can be no more than 12 weeks, including but notlimited to, no more than 11 weeks, no more than 10 weeks, no more than 9weeks, but preferably no more than 8 weeks, no more than 7 weeks, nomore than 6 weeks, no more than 5 weeks, no more than 4 weeks, or nomore than 3 weeks, e.g., the duration being 12 weeks, or the durationbeing 8 weeks. The total daily dosage of therapeutic agent 1 can be, butis not limited to, for example, about 100 mg, about 110 mg, about 120mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can beadministered in connection with therapeutic agent 1 with therapeuticagent 1 being administered at any of the dosages described above.Therapeutic agent 3 can be provided in combination with therapeuticagent 1. The total daily dosage of therapeutic agent 3 can be, but isnot limited to, for example, about 300 mg, about 310 mg, about 320 mg,about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg,about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg,about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg,about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg,about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg,about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg,about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg,about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirincan be administered either at the same time or at a separate time thantherapeutic agent 1 and therapeutic agent 3; and therapeutic agent 1 andtherapeutic agent 3 can be administered in any combination of thesuitable dosages recited above. Suitable total daily dosages ofribavirin can be based on the weight of the patient and include, but arenot limited to, from about 800 mg to about 1200 mg, including, forexample, about 1000 mg per day for a patient <75 kg or about 1200 mg perday for a patient ≧75 kg. In some embodiments, ritonavir can be eitherco-administered or administered separately with therapeutic agent 1.Suitable dosages of ritonavir include, from about 50 mg to about 400 mgper day, preferably about 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with HCV infection who are not candidates forinterferon treatment. The methods comprise administering to such apatient a combination of at least 2 DAAs and ribavirin for no more than12 weeks (e.g., the duration being 12 weeks), preferably no more than 8weeks (e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 3 and ribavirin. Patients who arenot candidates for interferon treatment include, but are not limited to,one or more of the following groups: patients intolerant to interferon,patients who refuse to take interferon treatment, patients with medicalconditions which preclude them from taking interferon, and patients whohave an increased risk of side effects or infection by takinginterferon. In some embodiments, the patient is infected with HCVgenotype 1, such as genotype 1a. In some embodiments, the patient isinfected with HCV genotype 1b. In some other embodiments, the patient isinfected with HCV genotype 2 or 3, such as 2a or 2b. In some otherembodiments, the patient is infected with HCV genotype 3a. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. The treatment duration can be no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably patients who are morethan 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the durationbeing 12 week, or the duration being 8 weeks. The total daily dosage oftherapeutic agent 1 can be, but is not limited to, for example, about100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.Therapeutic agent 3 can be administered with therapeutic agent 1 withtherapeutic agent 1 being administered at any of the dosages describedabove. Therapeutic agent 3 can be provided in combination withtherapeutic agent 1. The total daily dosage of therapeutic agent 3 canbe, but is not limited to, for example, about 300 mg, about 310 mg,about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg,about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg,about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg,about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg,about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg,about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg,about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg,about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000mg. Ribavirin can be administered either at the same time or at aseparate time than therapeutic agent 1 and therapeutic agent 3; andtherapeutic agent 1 and therapeutic agent 3 can be administered in anycombination of dosages of therapeutic agent 1 and therapeutic agent 3recited above. Suitable total daily dosages of ribavirin can be based onthe weight of the patient and include, but are not limited to, fromabout 800 mg to about 1200 mg, including, for example, about 1000 mg perday for a patient <75 kg or about 1200 mg per day for a patient ≧75 kg.In some embodiments, ritonavir can be either co-administered oradministered separately with therapeutic agent 1. Suitable dosages ofritonavir include, from about 50 mg to about 400 mg per day, preferablyabout 100 mg per day.

In some embodiments, the present technology features methods fortreating patients with HCV genotype 1, such as 1a or 1b, infection. Themethods comprise administering to such a patient a combination of atleast 2 DAAs and ribavirin for no more than 12 weeks (e.g., the durationbeing 12 weeks), preferably no more than 8 weeks (e.g., the durationbeing 8 weeks), wherein the treatment does not include administration ofinterferon. The combination comprises therapeutic agent 1, therapeuticagent 4 and ribavirin. Patients with genotype 1a or 1b infection can betreated with a combination of at least 2 DAAs without interferon inwhich the at least two DAAs include therapeutic agent 1 and therapeuticagent 4 with ribavirin. Therapeutic agent 1 and therapeutic agent 4 canbe administered in therapeutically effective amounts to provide a SVR(for example, a SVR8, SVR12, SVR16, or SVR24) in a treatment duration ofno more than 12 weeks, preferably no more than 8 weeks. The patients maybe treatment naïve patients or treatment experienced patients. Thetreatment duration can be no more than 12 weeks, including but notlimited to, no more than 11 weeks, no more than 10 weeks, no more than 9weeks, but preferably no more than 8 weeks, no more than 7 weeks, nomore than 6 weeks, no more than 5 weeks, no more than 4 weeks, or nomore than 3 weeks, e.g., the duration being 12 weeks, or the durationbeing 8 weeks. The total daily dosage of therapeutic agent 1 can be, butis not limited to, for example, about 100 mg, about 110 mg, about 120mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can beadministered in connection with therapeutic agent 1 where therapeuticagent 1 is administered in any of the dosages described above.Therapeutic agent 4 can be provided in combination with therapeuticagent 1 in a total daily dose of therapeutic agent 4 of from about 25 mgto about 200 mg. The total daily dosage of therapeutic agent 4 can be,but is not limited to, for example, about 20 mg, about 25 mg, about 30mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg,about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg,about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg,about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg,about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg,about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg,about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In someembodiments, ritonavir can be either co-administered or administeredseparately with therapeutic agent 1. Suitable dosages of ritonavirinclude, from about 50 mg to about 400 mg per day, preferably about 100mg per day. In suitable embodiments, therapeutic agent 1 and therapeuticagent 4 are administered once a day. Suitably, ribavirin may beadministered in connection with therapeutic agent 1 and therapeuticagent 4 where therapeutic agent 1 and therapeutic agent 4 areadministered in any combination of the suitable dosages detailed above.Suitable total daily dosages of ribavirin can be based on the weight ofthe patient and include, but are not limited to, from about 800 mg toabout 1200 mg, including, for example, about 1000 mg per day for apatient <75 kg or about 1200 mg per day for a patient ≧75 kg.

In some embodiments the present technology features methods for treatingpatients with HCV infection. The methods comprise administering to sucha patient a combination of at least 2 DAAs and ribavirin for no morethan 12 weeks (e.g., the duration being 12 weeks), preferably no morethan 8 weeks (e.g., the duration being 8 weeks), wherein the treatmentdoes not include administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 4 and ribavirin. The patients maybe treatment naïve patients or treatment experienced patients. Thetreatment can be administered for a duration of no more than 12 weeks,including but not limited to, no more than 11 weeks, no more than 10weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks. The patient can have HCV genotype1, such as HCV genotype 1a or 1b. In other embodiments, the patient mayhave HCV genotype 1b. In some embodiments, it is contemplated to treatother HCV genotypes. The total daily dosage of therapeutic agent 1 canbe, but is not limited to, for example, about 100 mg, about 110 mg,about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg,about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can beadministered in connection with therapeutic agent 1 in any of thedosages described above. Therapeutic agent 4 can be provided alone or incombination with therapeutic agent 1. The total daily dosage oftherapeutic agent 4 can be, but is not limited to, for example, about 15mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg,about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about340 mg, or about 350 mg. In some embodiments, ritonavir can be eitherco-administered or administered separately with therapeutic agent 1.Suitable dosages of ritonavir include, from about 50 mg to about 400 mgper day, preferably about 100 mg per day. In suitable embodiments,therapeutic agent 1 and therapeutic agent 4 are administered once a day.In some embodiments, therapeutic agent 1 and therapeutic agent 4 areadministered with ribavirin. Suitable total daily dosages of ribavirincan be based on the weight of the patient and include, but are notlimited to, from about 800 mg to about 1200 mg, including, for example,about 1000 mg per day for a patient <75 kg or about 1200 mg per day fora patient ≧75 kg.

In some embodiments, the present technology features methods fortreating patients with HCV infection. The methods comprise administeringto such a patient a combination of at least 2 DAAs and ribavirin for nomore than 12 weeks (e.g., the duration being 12 weeks), preferably nomore than 8 weeks (e.g., the duration being 8 weeks), wherein thetreatment does not include administration of interferon. The combinationcomprises therapeutic agent 1, therapeutic agent 4 and ribavirin. Thepatients may be treatment naïve patients or treatment experiencedpatients. The treatment can be administered for a duration of no morethan 12 weeks, including but not limited to, no more than 11 weeks, nomore than 10 weeks, no more than 9 weeks, but preferably no more than 8weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks,no more than 4 weeks, or no more than 3 weeks, e.g., the duration being12 weeks, or the duration being 8 weeks. The patient can have HCVgenotype 2 or 3, such as HCV genotype 2a. In some embodiments, thepatient may have HCV genotype 2b. In other embodiments the patient mayhave HCV genotype 3a. The total daily dosage of therapeutic agent 1 canbe, but is not limited to, for example, about 100 mg, about 110 mg,about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg,about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can beadministered in connection with therapeutic agent 1 in which therapeuticagent 1 is administered in any of the dosages described above.Therapeutic agent 4 can be provided in combination with therapeuticagent 1. The total daily dosage of therapeutic agent 4 can be, but isnot limited to, for example, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In someembodiments, ritonavir can be either co-administered or administeredseparately with therapeutic agent 1. Suitable dosages of ritonavirinclude, from about 50 mg to about 400 mg per day, preferably about 100mg per day. In suitable embodiments, therapeutic agent 1 and therapeuticagent 4 are administered once a day.

In some embodiments, therapeutic agent 1 and therapeutic agent 4 areadministered with ribavirin. Suitable total daily dosages of ribavirincan be based on the weight of the patient and include, but are notlimited to, from about 800 mg to about 1200 mg, including, for example,about 1000 mg per day for a patient <75 kg or about 1200 mg per day fora patient ≧75 kg.

In some embodiments, the present technology features methods fortreating patients with HCV infection who are not candidates forinterferon treatment. The methods comprise administering to such apatient a combination of at least 2 DAAs and ribavirin for no more than12 weeks (e.g., the duration being 12 weeks), preferably no more than 8weeks (e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. The combination comprisestherapeutic agent 1, therapeutic agent 4 and ribavirin. Patients who arenot candidates for interferon treatment include, but are not limited toone or more of the following groups: patients intolerant to interferon,patients who refuse to take interferon treatment, patients with medicalconditions which preclude them from taking interferon, and patients whohave an increased risk of side effects or infection by takinginterferon. In some embodiments, the patient is infected with HCVgenotype 1, such as genotype 1a. In some embodiments, the patient isinfected with HCV genotype 1b. In some other embodiments, the patient isinfected with HCV genotype 2 or 3, such as 2a or 2b. In some otherembodiments, the patient is infected with HCV genotype 3a. The treatmentaccording to this aspect of the technology can also be effective againstother HCV genotypes. Therapeutic agent 1 and therapeutic agent 4 can beadministered in therapeutically effective amounts to provide a SVR (forexample, a SVR8, SVR12, SVR16 or SVR24) after treatment of no more than12 weeks, preferably no more than 8 weeks. The interferon non-responderpatients include partial interferon responders and interferon reboundpatients. See GUIDANCE FOR INDUSTRY—CHRONIC HEPATITIS C VIRUS INFECTION:DEVELOPING DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, September2010, draft guidance) for the definitions of naive, partial responder,responder relapser (i.e., rebound), and null responder patients. Theinterferon non-responder patients also include null responder patients.The treatment can be administered for a duration of no more than 12weeks, including but not limited to, no more than 11 weeks, no more than10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, nomore than 7 weeks, no more than 6 weeks, no more than 5 weeks, no morethan 4 weeks, or no more than 3 weeks, e.g., the duration being 12weeks, or the duration being 8 weeks. The total daily dosage oftherapeutic agent 1 can be, but is not limited to, for example, about100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.Therapeutic agent 4 can be administered with therapeutic agent 1 wheretherapeutic agent 1 is administered in any of the dosages describedabove. Therapeutic agent 4 can be provided in combination withtherapeutic agent 1. The total daily dosage of therapeutic agent 4 canbe, but is not limited to, for example, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. Insome embodiments, ritonavir can be either co-administered oradministered separately with therapeutic agent 1. Suitable dosages ofritonavir include, from about 50 mg to about 400 mg per day, preferablyabout 100 mg per day. In suitable embodiments, therapeutic agent 1 andtherapeutic agent 4 are administered once a day. Suitably, ribavirin maybe administered in connection with therapeutic agent 1 and therapeuticagent 4 where therapeutic agent 1 and therapeutic agent 4 areadministered in any combination of suitable dosages as described above.Suitable total daily dosages of ribavirin can be based on the weight ofthe patient and include, but are not limited to, from from about 800 mgto about 1200 mg, including, for example, about 1000 mg per day for apatient <75 kg or about 1200 mg per day for a patient ≧75 kg.

In some embodiments, the present technology features methods fortreating patients with HCV infection who are interferon non-responders(e.g., null responders). The methods comprise administering to such apatient a combination of at least 2 DAAs and ribavirin for no more than12 weeks (e.g., the duration being 12 weeks), preferably no more than 8weeks (e.g., the duration being 8 weeks), wherein the treatment does notinclude administration of interferon. Interferon nonresponder patientscan be treated with a combination of at least 2 DAAs without interferonwith ribavirin wherein the two DAAs include therapeutic agent 1 andtherapeutic agent 4 with ribavirin. Therapeutic agent 1 and therapeuticagent 4 can be administered in therapeutically effective amounts toprovide a SVR (for example, a SVR8, SVR12, SVR16 or SVR24) aftertreatment duration of no more than 12 weeks, preferably no more than 8weeks. The interferon non-responder patients include partial interferonresponders and interferon rebound patients. The interferon nonresponderpatient may have HCV genotype 1, such as 1a. The interferon nonresponderpatient may have HCV genotype 1b. The interferon nonresponder patientcan have HCV genotype 2 or 3, such as HCV genotype 2a. In someembodiments, the patient may have HCV genotype 2b. In other embodimentsthe patient may have HCV genotype 3a. In some embodiments, it iscontemplated to treat other HCV genotypes. The treatment can beadministered for a duration of no more than 12 weeks, including but notlimited to, no more than 11 weeks, no more than 10 weeks, no more than 9weeks, but preferably no more than 8 weeks, no more than 7 weeks, nomore than 6 weeks, no more than 5 weeks, no more than 4 weeks, or nomore than 3 weeks, e.g., the duration being 12 weeks, or the durationbeing 8 weeks. The total daily dosage of therapeutic agent 1 can be, butis not limited to, for example, about 100 mg, about 110 mg, about 120mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can beadministered with therapeutic agent 1 wherein therapeutic agent 1 isadministered in any of the dosages described above. Therapeutic agent 4can be provided in combination with therapeutic agent 1. The total dailydosage of therapeutic agent 4 can be, but is not limited to, forexample, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg,about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg,about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg,about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg,about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg,about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg,about 330 mg, about 340 mg, or about 350 mg. In some embodiments,ritonavir can be either co-administered or administered separately withtherapeutic agent 1. Suitable dosages of ritonavir include, from about50 mg to about 400 mg per day, preferably about 100 mg per day. Insuitable embodiments, therapeutic agent 1 and therapeutic agent 4 areadministered once a day. Suitably, ribavirin may be administered inconnection with therapeutic agent 1 and therapeutic agent 4 whereintherapeutic agent 1 and therapeutic agent 4 are administered in anycombination of suitable dosages as described above. Suitable total dailydosages of ribavirin can be based on the weight of the patient andinclude, but are not limited to, from about 800 mg to about 1200 mg,including, for example, about 1000 mg per day for a patient <75 kg orabout 1200 mg per day for a patient ≧75 kg.

Accordingly, in some embodiments, the present technology features amethod of treating HCV infection, comprising administering to a patientin need thereof an effective amount of a combination of two or moreDAAs, together with an effective amount of ribavirin. The treatmentlasts no more than 12 weeks, alternatively no more than 11 weeks,alternatively no more than 10 weeks, alternatively no more than 9 weeks,preferably no more than 8 weeks, alternatively no more than 7 weeks,alternatively no more than 6 weeks, alternatively no more than 5 weeks,alternatively no more than 4 weeks, alternatively no more than 3 weeksand does not include administration of any interferon. The DAAs andribavirin can be administered at the same or different dosingfrequencies. The patient being treated can be an HCV-treatment naïvepatient or HCV-treatment experienced patient, including, interferonnon-responders, interferon partial responders (patients whose HCV RNAlevels declined but never became undetectable when treated withinterferon), or relapsers (patients who achieved undetectable levels ofHCV RNA during therapy but rebound) or a patient unable to takeinterferon. The patient can be infected with, for example and withoutlimitation, HCV genotypes 1 or 2. In some embodiments are preferablygenotypes 1a or 1b. In other embodiments, the HCV genotype is 2 or 3.Each DAA can be selected from HCV protease inhibitors, HCV polymeraseinhibitors, or HCV NS5A inhibitors.

For instance, the combination of two or more DAAs can be a combinationof at least one HCV protease inhibitor and at least one HCV polymeraseinhibitor (e.g., a combination of at least one HCV protease inhibitorand at least one non-nucleoside polymerase inhibitor, or a combinationof at least one HCV protease inhibitor and at least one nucleoside ornucleotide polymerase inhibitor, or a combination of at least one HCVprotease inhibitor, at least one nucleoside or nucleotide polymeraseinhibitor and at least one non-nucleoside inhibitor).

For another instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor and at least one HCVNS5A inhibitor. In an example, the combination of two or more DAAscomprises GS-5885 (an NS5A inhibitor), and GS-9451 (a protease inhibitoror an NS3 protease inhibitor). In some examples, GS-5885 is provided ina daily dose from about 3 mg to about 200 mg, alternatively from about 3mg to about 100 mg, alternatively from about 30 mg to about 90 mg,including, but not limited to, for example, about 3 mg, about 5 mg,about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg,about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, orabout 200 mg. GS-9451 can be administered in combination with any of thedaily dosages of GS-5885 described above. GS-9451 can be administered ina total daily dose from about 100 mg to about 500 mg, alternatively fromabout 200 mg to about 400 mg, including, but not limited to, forexample, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about300 mg, about 400 mg, or about 500 mg. Suitably examples include totaldaily dosages of about 30 mg GS-5885 and about 200 mg GS-9451;alternatively about 60 mg GS-5885 and about 200 mg GS-9451;alternatively about 90 mg GS-5885 and about 200 mg GS-9451.

In another instance, the present technology provides the at least twoDAAs comprise at least two HCV polymerase inhibitors. In someembodiments, the at least two HCV polymerase inhibitors comprise atleast one nucleoside or nucleotide analog polymerase inhibitor. In someembodiments, the at least two HCV polymerase inhibitors comprise atleast two nucleoside or nucleotide analog polymerase inhibitors.Suitable nucleotide analog polymerase inhibitors include PSI-7977(Pharmasset) and PSI-938 (Pharmasset). Suitable daily dosages of the atleast one nucleoside or nucleotide analog polymerase inhibitor includefrom about 100 mg to about 500 mg, alternatively from about 200 mg toabout 400 mg, including, but not limited to, for example, about 100 mg,about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg,about 400 mg, about 450 mg, or about 500 mg. For example, a suitablecombination includes a total daily dose of PSI-7977 of about 400 mg anda total daily of PSI-938 of about 300 mg, alternatively a total dailydose of about 200 mg PSI-7977 and a total daily dose of about 300 mgPSI-938. Suitably, ribavirin can be administered with the at least twoDAAs, preferably in an amount based on weight of the subject, in a totaldaily dose of from about 400 mg to about 1400 mg, suitably about 1000 mgor about 1200 mg per day. For example, a suitable ribavirin dailytreatment is weight based, for example, 1000 mg/day<75 kg and 1200mg/day≧75 kg, divided twice daily (BID). In yet another instance, thecombination of two or more DAAs comprises at least one HCV proteaseinhibitor and at least one HCV polymerase inhibitor. In someembodiments, the at least one protease inhibitor is TMC-435 (Medivir)and the at least one polymerase inhibitor is a nucleotide/nucleosideanalog polymerase inhibitor, for example PSI-7977. Suitably, the atleast one protease inhibitor, e.g. TMC-435, is provided in a total dailydosage from about 25 mg to about 250 mg, alternatively from about 25 mgto about 200 mg, alternatively from about 50 mg to about 200 mg,alternatively from about 75 mg to about 150 mg, for example, about 25mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,about 175 mg, or about 200 mg; and the at least one polymerase inhibitor(e.g. PSI-7977) is provided in a total daily dose from about 100 mg toabout 500 mg, alternatively from about 200 mg to about 400 mg,including, but not limited to, for example, about 100 mg, about 150 mg,about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,about 450 mg, or about 500 mg. For example, a combination can be a totaldaily dosage of about 75 mg TMC-435 and about 400 mg PSI-7977,alternatively about 100 mg TMC-435 and about 400 mg PSI-7977,alternatively about 150 mg TMC-435 and about 400 mg PSI-7977,alternatively about 100 mg TMC-435 and about 400 mg PSI-7977,alternatively about 75 mg TMC-435 and about 200 mg PSI-7977,alternatively about 150 mg TMC-435 and about 200 mg PSI-7977,alternatively about 100 mg TMC-435 and about 200 mg PSI-7977,alternatively about 75 mg TMC-435 and about 100 mg PSI-7977,alternatively about 100 mg TMC-435 and about 100 mg PSI-7977,alternatively about 150 mg TMC-435 and about 100 mg PSI-7977, and caninclude other suitable combinations. Suitably, in some embodiments,ritonavir or a suitable equivalent can be added to the at least two DAAscomprising at least one protease inhibitor, suitably in an amount fromabout 100 mg to about 400 mg per day, preferably about 100 mg per day.Suitable ribavirin can be administered with the at least two DAAs,preferably in an amount based on weight of the subject, suitably about1000 mg or about 1200 mg per day. For example, a suitable ribavirindaily treatment is weight based, for example, 1000 mg/day<75 kg and 1200mg/day≧75 kg, divided twice daily (BID). In alternative embodiments, theat least one protease is BI-201335 (NS3/4A protease inhibitor) and theat least one HCV polymerase inhibitor is a non-nucleoside polymeraseinhibitor, e.g. BI-207127. In some examples, the BI-201335 is providedin a total daily dose from about 100 mg to about 400 mg, alternativelyfrom about 120 mg to about 240 mg, including about 100 mg, about 120 mg,about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg,about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg,about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 275 mg,about 300 mg, about 320 mg, about 330 mg, about 350 mg, about 360 mg,about 370 mg, about 380 mg, or about 400 mg; and BI-207127 can beadministered in a total daily dose from about 300 mg to about 3600 mg,preferably from about 1200 mg to about 2100 mg, including, but notlimited to, for example, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about1000 mg, about 1100, about 1200 mg, about 1300 mg, about 1400 mg, about1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg,about 2000 mg, about 2100 mg, about 2200 mg, about 2400 mg, about 2500mg, about 2600 mg, about 2700 mg, about 2800 mg, about 3000 mg, about3200 mg, about 3400 mg, or about 3600 mg. Suitable examples, include,but are not limited to, a combination of a total daily dose of about 120mg BI-201335 and about 1200 mg BI-207127, alternatively about 120 mgBI-201335 and about 1500 mg BI-207127, alternatively about 120 mgBI-201335 and about 1800 mg BI-207127, alternatively about 120 mgBI-201335 and about 2100 mg BI-207127, alternatively about 240 mgBI-201335 and about 1200 mg BI-207127, alternatively about 240 mgBI-201335 and about 1500 mg BI-207127, alternatively about 240 mgBI-201335 and about 1800 mg BI-207127, alternatively about 240 mgBI-201335 and about 2100 mg BI-207127. Suitably, in some embodiments,ritonavir or a suitable equivalent can be added to the at least two DAAscomprising at least one protease inhibitor, suitably in an amount ofabout 100 mg per day. Suitably, in some embodiments, ritonavir or asuitable equivalent can be added to the at least two DAAs comprising atleast one protease inhibitor, suitable in an amount from about 100 mg toabout 400 mg per day, preferably about 100 mg per day. Suitableribavirin can be administered with the at least two DAAs, preferably inan amount based on weight of the subject, suitably from about 400 mg toabout 1400 mg per day, for example, about 1000 mg or about 1200 mg perday. For example, a suitable ribavirin daily treatment is weight based,for example, from 400 mg to about 1400 mg, preferably about 1000mg/day<75 kg and 1200 mg/day≧75 kg, divided twice daily (BID). In yetanother example, the combination of two or more DAAs comprisestelaprevir (VX-950, protease inhibitor) and VX-222 (non-nucleosidepolymerase inhibitor). In some examples, the telaprevir is provided intotal daily doses from about 1000 mg to about 2500 mg, alternativelyfrom about 2000 mg to about 2500 mg, including, but not limited to, forexample, about 1000 mg, about 1200 mg, about 1300 mg, about 1500 mg,about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2400 mg, about2500 mg. VX-222 can be administered with telaprevir in any combinationwith the dosage amounts of telaprevir provided above. VX-222 can beprovided in a total daily dosage from about 100 mg to about 1000 mg,alternatively from about 200 mg to about 800 mg, including, but notlimited to, for example, about 100 mg, about 200 mg, about 300 mg, about400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about900 mg, or about 1000 mg. In some examples, telaprevir can be a totaldaily dose of about 2250 mg and VX-222 can be a total daily dose ofabout 100 mg, alternatively telaprevir can be a total daily dose ofabout 2250 mg and VX-222 can be a total daily dose of about 200 mg,alternatively telaprevir can be a total daily dose of about 2250 mg andVX-222 can be a total daily dose of about 400 mg, alternativelytelaprevir can be a total daily dose of about 2250 mg and VX-222 can bea total daily dose of about 600 mg, alternatively telaprevir can be atotal daily dose of about 2250 mg and VX-222 can be a total daily doseof about 800 mg, alternatively telaprevir can be a total daily dose ofabout 1500 mg and VX-222 can be a total daily dose of about 200 mg,alternatively telaprevir can be a total daily dose of about 1500 mg andVX-222 can be a total daily dose of about 400 mg, alternativelytelaprevir can be a total daily dose of about 1500 mg and VX-222 can bea total daily dose of about 800 mg. Suitably, telaprevir can beadministered three times a day (TID), for example 3 times a day with 750mg per dose. Other suitable daily dosage of telaprevir is 1125 mg twicea day (BID). Suitably, in some embodiments, ritonavir or a suitableequivalent can be added to the at least two DAAs comprising at least oneprotease inhibitor, suitably in an amount of about 100 mg to about 400mg per day, preferably about 100 mg per day. Suitable ribavirin can beadministered with the at least two DAAs, preferably in an amount basedon weight of the subject, from about 400 mg to about 1400 mg, suitablyabout 1000 mg or about 1200 mg per day. For example, a suitableribavirin daily treatment is weight based, for example, 1000 mg/day<75kg and 1200 mg/day≧75 kg, divided twice daily (BID).

In yet another example, the combination of two or more DAAs includesdanoprevir (protease inhibitor) and R7128 (nucleoside polymeraseinhibitor). In some embodiments, danoprevir can be administered in atotal daily dosage from about 100 mg to about 2000 mg, alternativelyfrom about 200 mg to about 1800 mg, alternatively from about 400 mg toabout 1800 mg, including, but not limited to, for example, about 100 mg,about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg,about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg,about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600mg, about 1700 mg, about 1800 mg, and other amounts therebetween. R7128can be administered in a total daily dose from about 100 mg to about2000 mg, alternatively from about 200 mg to about 2000 mg, alternativelyfrom about 1000 mg to about 2000 mg, including, but not limited to, forexample, about 150 mg, about 200 mg, about 400 mg, about 500 mg, about600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg,about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In someexamples, the total daily dose of the danoprevir is about 200 mg and thetotal daily dose of R7128 is about 200 mg, alternatively the total dailydoses of the danoprevir is about 400 mg and the total daily dose ofR7128 is about 200 mg, alternatively, the total daily dose of thedanoprevir is about 1000 mg and the total daily dose of R7128 at about200 mg, alternatively the total daily dose of the danoprevir is about1800 mg and the total daily dose of R7128 is about 200 mg, alternativelythe total daily dose of the danoprevir is about 2000 mg and the totaldaily dose of R7128 is about 200 mg, alternatively the total daily doseof the danoprevir is about 400 mg and the total daily dose of R7128 isabout 400 mg, alternatively, the total daily dose of the danoprevir isabout 1000 mg and the total daily dose of R7128 is about 400 mg,alternatively the total daily dose of the danoprevir is about 2000 mgand the total daily dose of R7128 is about 400 mg, alternatively thetotal daily dose of the danoprevir is about 1800 mg and the total dailydose of R7128 is about 400 mg, alternatively the total daily dose of thedanoprevir is about 400 mg and the total daily dose of R7128 is about1000 mg, alternatively, the total daily dose of the danoprevir is about1000 mg and the total daily dose of R7128 is about 1000 mg,alternatively the total daily dose of the danoprevir is about 2000 mgand the total daily dose of R7128 is about 1000 mg, alternatively thetotal daily dose of the danoprevir is about 1800 mg and the total dailydose of R7128 is about 1000 mg, alternatively the total daily dose ofthe danoprevir is about 400 mg and the total daily dose of R7128 isabout 2000 mg, alternatively, the total daily dose of the danoprevir isabout 1000 mg and the total daily dose of R7128 is about 2000 mg,alternatively the total daily dose of the danoprevir is about 2000 mgand the total daily dose of R7128 is about 2000 mg, alternatively thetotal daily dose of the danoprevir is about 1800 mg and the total dailydose of R7128 is about 2000 mg. In suitable embodiments, danoprevir andR7128 can be administered with ritonavir, suitably in an amount of about100 mg to about 400 mg per day, preferably about 100 mg per day.Suitable ribavirin can be administered with the at least two DAAs,preferably in an amount based on weight of the subject, from about 400mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day.For example, a suitable ribavirin daily treatment is weight based, forexample, 1000 mg/day<75 kg and 1200 mg/day≧75 kg, divided twice daily(BID).

In some other instances of the present technology, the combinations oftwo or more DAAs may be at least one protease inhibitor and at least oneNS5A inhibitor. In some examples, the at least one protease inhibitor isan NS3 protease inhibitor. In some embodiments, the at least oneprotease inhibitor and at least one NS5A inhibitor comprises BMS-650032(BMS) and BMS-790052 (BMS) respectively. In suitable embodiments,BMS-650032 can be administered in a total daily dose from about 300 mgto about 1500 mg, alternatively from about 500 mg to about 1500 mg,including, but not limited to, for example, about 300 mg, about 400 mg,about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg,about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400mg, and about 1500 mg, and BMS-790052 (BMS) can have a total daily dosefrom about 10 mg to about 200 mg, alternatively from about 50 mg toabout 100 mg, including, but not limited to, for example, about 10 mg,about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. Insuitable examples, BMS-650032 (BMS) total daily dose is about 1200 mgand BMS-790052 (BMS) total daily dose is about 60 mg, alternativelyBMS-650032 (BMS) total daily dose is about 300 mg and BMS-790052 (BMS)total daily dose is about 60 mg. Suitable ribavirin can be administeredwith the at least two DAAs, preferably in an amount based on weight ofthe subject, from about 400 mg to about 1400 mg, suitably about 1000 mgor about 1200 mg per day. For example, a suitable ribavirin dailytreatment is weight based, for example, 1000 mg/day<75 kg and 1200mg/day≧75 kg, divided twice daily (BID).

In some other instances of the present technology, the combinations oftwo or more DAAs may be at least one nucleoside or nucleotide polymeraseinhibitor, at least one protease inhibitor, and at least one NS5Ainhibitor. In some examples, the at least one protease inhibitor is anNS3 protease inhibitor. In some embodiments, the at least one nucleosideor nucleotide polymerase inhibitor is INX-189, the at least one proteaseinhibitor is BMS-650032 (asunaprevir), and the at least one NS5Ainhibitor comprises is BMS-790052 (daclatasivr). Such embodiments areespecially contemplated for treating a patient infected with HCVgenotype 1, such as genotype 1a or 1b (particularly genotype 1a), aswell as patients infected with other HCV genotypes, such as genotypes 2or 3. In suitable embodiments, INX-189 can be administered in a totaldaily dose from about 5 mg to about 400 mg, alternatively from about 25mg to about 200 mg, including but not limited to, for example, about 5mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300mg. In suitable embodiments, BMS-650032 can be administered in a totaldaily dose from about 300 mg to about 1500 mg, alternatively from about500 mg to about 1500 mg, including, but not limited to, for example,about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg,about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg,about 1300 mg, about 1400 mg, and about 1500 mg, and BMS-790052 (BMS)can have a total daily dose from about 10 mg to about 200 mg,alternatively from about 50 mg to about 100 mg, including, but notlimited to, for example, about 10 mg, about 20 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg,about 150 mg, or about 200 mg. In suitable examples, BMS-650032 (BMS)total daily dose is about 1200 mg and BMS-790052 (BMS) total daily doseis about 60 mg, alternatively BMS-650032 (BMS) total daily dose is about300 mg and BMS-790052 (BMS) total daily dose is about 60 mg. Suitableribavirin can be administered with the at least two DAAs, preferably inan amount based on weight of the subject, from about 400 mg to about1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, asuitable ribavirin daily treatment is weight based, for example, 1000mg/day<75 kg and 1200 mg/day≧75 kg, divided twice daily (BID).

For still another instance, the combination of two or more DAAs can be acombination of at least one HCV protease inhibitor, at least one HCVpolymerase inhibitor, and at least one HCV NS5A inhibitor. In anexample, the combination of two or more DAAs comprises GS-5885 (an NS5Ainhibitor), GS-9190 (tegobuvir, a non-nucleoside polymerase inhibitor),and GS-9451 (a protease inhibitor or a NS3 protease inhibitor). In someexamples, GS-5885 is provided in a daily dose from about 3 mg to about200 mg, alternatively from about 3 mg to about 100 mg, alternativelyfrom about 30 mg to about 90 mg, including, but not limited to, forexample, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170mg, about 180 mg, about 190 mg, or about 200 mg, and GS-9190 is providedin a daily dose from about 10 mg to about 100 mg, alternatively fromabout 30 mg to about 90 mg, including, but not limited to, for example,about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; andGS-9451 can be administered in a daily dose from about 100 mg to about500 mg, alternatively from about 200 mg to about 400 mg, including, butnot limited to, about 100 mg, about 150 mg, about 200 mg, about 250 mg,about 300 mg, about 400 mg, or about 500 mg. Suitably examples includeabout daily amounts of about 30 mg GS-5885, about 60 mg GS-9190 andabout 200 mg GS-9451; alternatively about 60 mg GS-5885, about 60 mgGS-9190, and about 200 mg GS-9451; alternatively about 90 mg GS-5885,about 60 mg GS-9190, and about 200 mg GS-9451. In some embodiments theGS-9190, GS-9451, and GS-5885 is administered with ritonavir or asuitable equivalent, suitably in an amount of about 100 mg to about 400mg per day, preferably about 100 mg per day. Suitable ribavirin can beadministered with the at least two DAAs, preferably in an amount basedon weight of the subject, from 400 mg to about 1400 mg, suitably about1000 mg or about 1200 mg per day. For example, a suitable ribavirindaily treatment is weight based, for example, 1000 mg/day<75 kg and 1200mg/day≧75 kg, divided twice daily (BID). For still another instance, thecombination of two or more DAAs can be a combination of at least one HCVprotease inhibitor, at least one HCV polymerase inhibitor, and at leastone HCV NS5A inhibitor.

In another embodiment, the present technology provides interferon-freetreatment comprising administering daily two DAAs with ribavirin, wherethe two DAAs include a HCV polymerase inhibitor, for example PSI-7977and a NS5A inhibitor, for example BMS-790052 for a duration of no morethan eleven weeks, preferably no more than eight weeks. PSI-7977 andBMS-790052 are administered in an effective amount to provide an SVR(for example, an SVR8, SVR12, SVR16, or SVR24) with a treatment durationof no more than eleven weeks, no more than ten weeks, no more than nineweeks, no more than eight weeks, no more than seven weeks, no more thansix weeks, no more than five weeks, no more than four weeks or no morethan three weeks. The patients can be treatment naïve patients ortreatment experienced patients. In some embodiments, the patients canhave HCV genotype 1, such as 1a or 1b. In some embodiments, the patientscan have genotype 2 or 3, such as 2a, 2b or 3a. PSI-7977 can be providedin a total daily dose of from about 100 mg to about 500 mg,alternatively from about 200 mg to about 400 mg, including, but notlimited to, for example, about 100 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about500 mg. BMS-790052 can be administered in combination with PSI-7977 atany daily dose of PSI-7977 provided above. BMS-790052 (BMS) can have atotal daily dose of from about 10 mg to about 200 mg, alternatively fromabout 50 mg to about 100 mg, including, but not limited to, about 10 mg,about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In onesuitable example, PSI-7977 is administered in a total daily dose of 400mg and BMS-790052 is administered in a total daily dose of 60 mg.

The chemical structures of some of these HCV inhibitors as reported bynumerous sources are provided below:

It has also been reported that BMS-791325 has the following structure:

See also publications athttp://www1.eas1.eu/eas12011/program/Posters/Abstract680.htm; andhttp://clinicaltrials.gov/show/NCT00664625. For GS-5885, seepublications at http://www.natap.org/2011/EASL/EASL_(—)68.htm;http://www1.eas1.eu/eas12011/program/Posters/Abstract1097.htm; andhttp://clinicaltrials.gov/ct2/show/NCT01353248.

Any HCV inhibitor or DAA described herein encompasses its suitable saltforms when it is used in therapeutic treatments or pharmaceuticalformulations.

The following table lists non-limiting examples of the treatmentregimens of the present technology. In each treatment regimen, the atleast two DAA with or without ritonavir, are administered daily to anHCV patient under such treatment. Each treatment is interferon-free.Administration of ribavirin is included in each regimen. Each treatmentregimen may also optionally comprise administering one or more otheradditional DAAs to the patient. The duration of each treatment regimenmay last, for example and without limitation, no more than 12 weeks, nomore than 11 weeks, no more than 10 weeks, no more than 9 weeks, no morethan 8 weeks, alternatively no more than 7 weeks, alternatively no morethan 6 weeks, alternatively no more than 5 weeks, alternatively no morethan 4 weeks and may depend on the patient's response. In any givenregimen described below, the drugs can be, for example and withoutlimitation, co-formulated in a single solid dosage form when each hasthe same dosing frequency.

For instance, two or more drugs in a regimen can be co-formulated inamorphous forms or molecularly dispersed in a matrix comprising awater-soluble polymer and optionally a surfactant; for another instance,therapeutic agent 1 and ritonavir (RTV) are formulated in an amorphousform or molecularly dispersed in a matrix comprising a water-solublepolymer and optionally a surfactant, and therapeutic agent 3 is combinedwith amorphous Compound 1 and RTV in a single solid dosage form. For yetanother instance, Compound 1 and RTV are formulated in a differentdosage form than that of therapeutic agent 3.

TABLE 1 Non-Limiting Examples of Interferon-free Treatment Regimens withtwo or more DAAs (without ribavirin** and with or without ritonavir)Regi- Drugs Used in men Treatment Suitable total daily dosages 1Therapeutic Agent 1*+ 150 to 250 mg (pref. 150, 200, 250 mg) TherapeuticAgent 4 5 mg to 300 mg (pref. 25 mg) 2 Therapeutic Agent 1*+ 150 to 250mg (pref. 150, 200, 250 mg) Therapeutic Agent 4+ 5 mg to 300 mg (pref.25 to 200 mg) Therapeutic Agent 2 300 to 1800 mg (pref. 400 mg or 800mg) 3 Therapeutic Agent 1*+ 150-250 mg (pref. 150 mg or 250 mg)Therapeutic Agent 3+ 50 mg-1000 mg (pref. 400 mg) Therapeutic Agent 4 5mg-300 mg (pref. 25 mg-200 mg, more pref. 25 mg) 4 Therapeutic Agent 1*+150-250 mg (150 mg, 200 mg or 250 mg) Therapeutic Agent 2 300-1800 mg(pref. 200 mg, 800 mg) 5 Therapeutic Agent 1*+ 50 mg to 250 mg (pref. 50mg or 250 mg) Therapeutic Agent 3 50 mg to 1000 mg (pref. 400 mg to 800mg) 6 PSI-7977+ 100 mg to 500 mg (pref. 200, 400 mg) PSI-938 100 mg to500 mg (pref. 300 mg) 7 BMS-790052+ 10 mg to 200 mg (pref. 60 mg)BMS-650032 300 mg to 1500 mg (pref. 1200 mg) 8 GS-5885+ 3 mg to 200 mg(pref. 30 mg to 90 mg) GS-9190+ 30 mg to 90 mg (pref. 60 mg) GS-9451 100mg to 500 mg (pref. 200 mg) 9 GS-5885+ 3 mg to 200 mg (pref. 30 to 90mg) GS-9451 100 mg to 500 mg (pref. 200 mg) 10 BI-201335+ 100 mg to 400mg (pref. 120 mg or 240 mg) BI-207127 300 mg to 3600 mg (pref. 1200 mgto 2100 mg) 11 PSI-7977+ 100 mg to 500 mg (pref. 400 mg) TMC-435 25 mgto 200 mg (pref. 75 mg to 150 mg) 12 telaprevir+ 1000 mg to 2500 mg(pref. 2250 mg) VX-222 200 mg to 800 mg 13 Danoprevir*+ 100 mg to 2000mg (pref. 200 mg or 400 mg) R7128 100 mg to 2000 mg (pref. 200 mg, 400mg, 1000 mg or 2000 mg) 14 Danoprevir+ 100 mg to 2000 mg (pref. 800 mgor 1000 mg, or 1800 mg or 2000 mg) R7128 100 mg to 2000 mg (pref. 200mg, 400 mg, 1000 mg or 2000 mg) 15 PSI-7977+ 100 mg to 500 mg (pref. 400mg) daclatasvir 10-200 mg (pref. 60 mg) (BMS-790052) 16 PSI-7977+ 100 mgto 2000 mg (pref. 1800 mg or 2000 mg) asunaprevir 300-1500 mg (pref.1200 mg) (BMS-650032) 17 PSI-7977+ 100 mg to 500 mg (pref. 400 mg)daclatasvir 10-200 mg (pref. 60 mg) (BMS-790052) asunaprevir 300-1500 mg(pref. 1200 mg) (BMS-650032) *ritonavir or a suitable equivalent can beadded to any one of these treatments as described and may be added toany of these treatments at a daily total dosage as described in thepresent technology; preferably ritonavir is co-formulated withtherapeutic agent 1 or danoprevir; the dose of ritonavir preferably is100 mg. Pref. = preferred **in each regimen, ribavirin preferably isused in a weight based amount from 400 mg to 1400 mg (pref. 1000 to 1200mg)

Additional non-limiting examples of interferon-free treatment regimenswith two or more DAAs, with ribavirin and with or without ritonavir or asuitable equivalent, including the following: (a) Therapeutic Agent 1 ata total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100mg) with ritonavir or a suitable equivalent, and Therapeutic Agent 4 ata total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100mg); (b) Therapeutic Agent 1 at a total daily dose of 5 mg to 200 mg(pref. 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitableequivalent, Therapeutic Agent 4 at a total daily dose of 5 mg to 200 mg(pref. 25 mg or 100 mg), and Therapeutic Agent 2 at a total daily doseof 200 mg to 800 mg (pref. 400 mg or 800 mg); (c) Therapeutic Agent 1 ata total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100mg) with ritonavir or a suitable equivalent, Therapeutic Agent 3 at atotal daily dose of 100 mg to 600 mg (pref. 400 mg), and TherapeuticAgent 4 at a total daily dose of 5 mg to 300 mg (pref. 25 mg to 200 mg,more pref. 25 mg); (d) Therapeutic Agent 1 at a total daily dose of 5 mgto 150 mg (pref. 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or asuitable equivalent, and Therapeutic Agent 2 at a total daily dose of200-800 mg; (e) GS-5885 at a total daily dose of 3-200 mg (pref. 30-90mg). GS-9190 at a total daily dose of 30-90 mg (pref. 60 mg), andGS-9451 at a total daily dose of 100-500 mg (pref. 200 mg); (f) GS-5885at a total daily dose of 3 mg to 200 mg (pref. 30 mg, 60 mg, or 90 mg),and GS-9451 at a total daily dose of 100 mg to 500 mg (pref. 200 mg);(g) BI-201335 at a total daily dose of 100 mg to 400 mg (pref. 120 mg,240 mg), and BI-207127 at a total daily dose of 300 mg to 3600 mg (pref.1200 or 1500 mg, 1800 mg or 2100 mg); (h) PSI-7977 at a total daily doseof 100 mg to −500 mg (pref. 100, 200 mg), and TMC-435 at a total dailydose of 25 mg to 200 mg (pref. 75 mg, 100 mg, or 150 mg); (i) telaprevirat a total daily dose of 1000 mg to 2500 mg (pref. 1500 mg or 2250 mg),and VX-222 at a total daily dose of 100 mg to 800 mg (pref. 100 mg, 200mg, 400 mg, 600 mg or 800 mg); (j) INX-189 at a total daily dose of 5 mgto 400 mg (pref. 50 mg, 100 mg or 200 mg), and daclatasvir (BMS-790052)at a total daily dose of 10 mg to 200 mg (pref. 60 mg); (k) INX-189 at atotal daily dose of 5 mg to 400 mg (pref. 50 mg, 100 mg or 200 mg), andasunaprevir (BMS-650032) at a total daily dose of 300 mg to 1500 mg(pref. 1200 mg); and (1) INX-189 at a total daily dose of 5 mg to 400 mg(pref. 50 mg, 100 mg or 200 mg), daclatasvir (BMS-790052) at a totaldaily dose of 10 mg to 200 mg (pref. 60 mg), and asunaprevir(BMS-650032) at a total daily dose of 300 mg to 1500 mg (pref. 1200 mg).In any of these examples, ritonavir or a suitable equivalent can beadded to any one of these treatments as described and may be added toany of these treatments at a daily total dosage as described in thepresent technology; preferably ritonavir is co-formulated withtherapeutic agent 1 or danoprevir; the dose of ritonavir preferably is100 mg. In these examples, ribavirin preferably is used in a weightbased amount from 400 mg to 1400 mg (pref. 1000 to 1200 mg).

The treatments of the present technology may be effective in treatingHCV infection against HCV genotypes 1, 2, 3, 4, 5, 6, includingsubgenotypes, such as 1a, 1b, 2a, and 3a.

In general and depending on patients' conditions, the total daily doseof the DAAs of the present technology may be administered (either as asingle or divided dose) in amounts from about 0.001 mg/kg to about 200mg/kg, or from about 0.001 mg/kg to about 30 mg/kg, or from about 0.001mg/kg to about 30 mg/kg, or from about 0.01 mg/kg, to about 10 mg/kg(i.e. mg of the compound or salt per kg body weight), and include anyamounts or ranges there between, including, but not limited toincrements of 0.001 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.05 mg/kg, andmultiple factors thereof (e.g. 0.25×, 0.5×, 1×, 2×, 3×, 5×, 10×, 100×,etc.). Suitable dosages of the DAAs of the present technology include,but are not limited to, from about 25 mg to about 2000 mg, from about 25mg to about 1500 mg, from about 25 mg to about 1600 mg, from about 25 mgto about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg toabout 500 mg, from about 25 mg to about 250 mg, from about 50 mg toabout 2000 mg, from about 50 mg to about 1500 mg, from about 50 mg toabout 1600 mg, from about 50 mg to about 1000 mg, from about 50 mg toabout 800 mg, from about 50 mg to about 500 mg, from about 50 mg toabout 250 mg, and include, but are not limited to, for example, about 25mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130mg, about 140 mg, about 150 mg, about 160 mg, about 165 mg, about 170mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220mg, about 230 mg, about 250 mg, and includes any increments therebetween, including increments of about 1 mg, about 2 mg, about 3 mg,about 4 mg, about 5 mg, about 6 mg, about 10 mg, about 15 mg, about 20mg, about 25, and multiples thereof (e.g. 0.25×, 0.5×, 1×, 2×, 3×, 5×,10×, 100×, etc.). It will be understood, however, that the specific doselevel for any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe disease undergoing therapy.

The cytochrome P-450 inhibitor may be administered in any suitableamount such as, for example, in doses of from about 0.3 mg/kg to about 2mg/kg or from about 0.6 mg/kg to about 1.5 mg/kg. As non-limitingexamples, the cytochrome P-450 inhibitor may be administered in a totaldaily dose amount of from about 25 mg to about 300 mg, or from about 50mg to about 250 mg, or from about 100 mg to about 200 mg. In someembodiments, the cytochrome P-450 inhibitor is administered in a totaldaily dose of about 100 mg to about 400 mg, preferably about 100 mg. Insome embodiments, the cytochrome P-450 inhibitor is administered in atotal daily dose amount of about 25 mg. In some embodiments, thecytochrome P-450 inhibitor is administered in a total daily dose amountof about 50 mg. In some embodiments, the cytochrome P-450 inhibitor isadministered in a total daily dose amount of about 75 mg. In someembodiments, the cytochrome P-450 inhibitor is administered in a totaldaily dose amount of about 100 mg. In some embodiments, the cytochromeP-450 inhibitor is administered in a total daily dose amount of about125 mg.

The one or more DAAs and ribavirin can be administered, for example andwithout limitation, concurrently or sequentially, and at the same ordifferent frequencies. For instance, For example, one DAA can beadministered immediately before or after the administration of anotherDAA. A short delay or time gap may exist between the administration ofone DAA and that of another DAA. The frequency of administration mayalso be different. For example, a first DAA may be administered once aday and a second DAA may be administered twice or three times a day. Forexample, a first DAA with or without ritonavir may be administered oncedaily, and a second DAA may be administered twice daily.

The DAAs of the present technology can be co-formulated in a singledosage form. Non-limiting examples of suitable dosage forms includeliquid or solid dosage forms. For example, a dosage form of Compound 1as a solid dosage form is described in U.S. Patent ApplicationPublication No. 2011/0312973, filed Mar. 8, 2011 and entitled “SolidCompositions”, the entire content of which is incorporated herein byreference. More preferably, the dosage form is a solid dosage form inwhich at least one of the DAAs is in an amorphous form, or highlypreferably molecularly dispersed, in a matrix which comprises apharmaceutically acceptable water-soluble polymer and a pharmaceuticallyacceptable surfactant. The other DAAs can also be in an amorphous formor molecularly dispersed in the matrix, or formulated in differentform(s) (e.g., in a crystalline form).

The DAAs of the present technology can be formulated in different dosageforms. It will be understood that the total daily dosage of thecompounds and compositions to be administered will be decided by theattending physician within the scope of sound medical judgment.

In one embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a dose of 150 mg once a day (QD),therapeutic agent 2 at a dose of 400 mg or 800 mg twice a day (BID),ritonavir at a dose of 100 mg once a day (QD), and an effective amountof ribavirin (for example, 1000 mg or 1200 mg, or an amount based on theweight of the subject) QD, for 12 weeks. At the end of treatment, thesubject has no detectable virus.

In one embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a dose of 50 mg QD, Therapeuticagent 2 at a dose of 400 mg or 800 mg BID, ritonavir at a dose of 100 mgQD, and an effective amount of ribavirin (for example, 1000 mg or 1200mg, or an amount based on the weight of the subject) QD, for 12 weeks.At the end of treatment, the subject has no detectable virus.

In one embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a dose of 250 mg QD, Therapeuticagent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, andan effective amount of ribavirin (for example, 1000 mg or 1200 mg, or anamount based on the weight of the subject) QD, for 12 weeks. At the endof treatment, the subject has no detectable virus.

In another embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a dose of 150 mg QD, Therapeuticagent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, andan effective amount of ribavirin (for example, 1000 mg or 1200 mg, or anamount based on the weight of the subject) QD, for 12 weeks. At the endof treatment, the subject has no detectable virus.

In yet another embodiment, a method for treating apeginterferon+ribavirin (P/RBV) non-responder comprises administeringTherapeutic agent 1 at a dose of 150 mg QD, Therapeutic agent 2 at adose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effectiveamount of ribavirin (for example, 1000 mg or 1200 mg, or an amount basedon the weight of the subject) QD, for 12 weeks. At the end of treatment,the subject has no detectable virus.

In yet another embodiment, a method for treating apeginterferon+ribavirin (P/RBV) non-responder comprises administeringTherapeutic agent 1 at a dose of 50 mg QD, Therapeutic agent 2 at a doseof 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amountof ribavirin (for example, 1000 mg or 1200 mg, or an amount based on theweight of the subject) QD, for 12 weeks. At the end of treatment, thesubject has no detectable virus.

In one embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a total daily dose of 150 mg QD,Therapeutic agent 3 at a total daily dose of 400 mg QD, ritonavir at adose of 100 mg QD, and an effective amount of ribavirin (for example,1000 mg or 1200 mg, or an amount based on the weight of the subject) QD,for 12 weeks. At the end of treatment, the subject has no detectablevirus.

In another embodiment, a method for treating a naïve subject comprisesadministering Therapeutic agent 1 at a total daily dose of 100 mg or 200mg QD, Therapeutic agent 4 at a total daily dose of 25 mg QD, ritonavirat a dose of 100 mg QD, and an effective amount of ribavirin (forexample, 1000 mg or 1200 mg, or an amount based on the weight of thesubject) QD, for 12 weeks. At the end of treatment, the subject has nodetectable virus.

In yet another embodiment, a method for treating a naïve subjectcomprises administering Therapeutic agent 1 at a total daily dose of 100mg or 150 mg QD, Therapeutic agent 2 at a total daily dose of 400 mgBID, Therapeutic agent 4 at a total daily dose of 25 mg QD, ritonavir ata dose of 100 mg QD, and an effective amount of ribavirin (for example,1000 mg or 1200 mg, or an amount based on the weight of the subject) QD,for 12 weeks. At the end of treatment, the subject has no detectablevirus.

It should be understood that the above-described embodiments and thefollowing examples are given by way of illustration, not limitation.Various changes and modifications within the scope of the presentinvention will become apparent to those skilled in the art from thepresent description.

EXAMPLE 1 Use of 2-DAA Combination with Ribavirin (RBV) to TreatTreatment-Naïve Subjects Infected with HCV Genotype 1

Previously untreated subjects having HCV infection were treated with aprotease inhibitor (in combination with ritonavir), a polymeraseinhibitor, and ribavirin. The treatment was without interferon.

Subjects included 11 treatment naïve, non-cirrhotic HCV genotype1-infected subjects between the ages of 18 and 65. All subjected hadIL28B CC genotype. All subjects completed 12 weeks of therapy withCompound 1 and ritonavir (Compound 1/r) dosed in combination withCompound 3 and ribavirin (RBV). Compound 1 (150 mg once daily (QD)) wasdosed with 100 mg QD ritonavir, 400 mg QD Compound 3, and weight-basedamounts of RBV (1,000-1,200 mg/day dosed twice daily) in treatment naïvesubjects infected with genotype (GT) 1 HCV.

HCV RNA levels were measured by TaqMan assay. Five of the elevensubjects had hepatitis C ribonucleic acid (HCV RNA)<25 IU/mL (i.e.,below the limit of quantification) at 2 weeks. Another five subjects hadundetectable levels of HCV RNA at 2 weeks. At week 3, three of theeleven subjects had HCV RNA levels of less than 25 IU/mL, and eightsubjects had undetectable levels of HCV RNA. Ten of the eleven subjectshad undetectable levels of HCV RNA at 4 weeks, and one subject had anHCV RNA level of less than 25 IU/mL. All eleven subjects hadundetectable levels of HCV RNA at 5 weeks. HCV RNA levels remainedundetectable in all subjects at week 6, 7, 8, 9, 10, 11 and 12. Allsubjects had undetectable levels of HCV RNA at post-treatment weeks 2and 4. At post-treatment weeks 8 and 12, a single subject had detectableHCV RNA (breakthrough), and the remaining 10 subjects did not have anydetectable level of HCV RNA. These remaining ten subjects were furthertested at post-treatment weeks 16 and 24, and all of them hadundetectable levels of HCV RNA at both timepoints. One of the remainingten subjects unexpectedly showed detectable HCV RNA at post-treatmentweek 36.

EXAMPLE 2 A Use of 2-DAA Combination with Ribavirin to TreatTreatment-Naïve or Non-Responder Subjects Infected with HCV Genotype 1

Group 1. Previously untreated subjects having HCV infection were treatedwith a protease inhibitor (in combination with ritonavir), a polymeraseinhibitor, and ribavirin. The treatment was without interferon.

Subjects included 19 treatment naïve subjects between the ages of 18 and65. One subject discontinued the study at week 3. All of the remaining18 subjects completed 12 weeks of therapy with Compound 1/r dosed incombination with Compound 2 and RBV. Compound 1 (250 mg QD) was dosedwith 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in treatmentnaïve subjects infected with GT1 HCV.

Group 2. Previously untreated subjects having HCV infection were treatedwith a protease inhibitor (in combination with ritonavir), a polymeraseinhibitor, and ribavirin. The treatment was without interferon.

Subjects included 14 treatment naïve subjects between the ages of 18 and65. One subject discontinued the study at week 1. Therefore, a total of13 subjects were under study. All of the thirteen subjects completed 12weeks of therapy with Compound 1/r dosed in combination with Compound 2and RBV. Compound 1 (150 mg QD) was dosed with 100 mg QD ritonavir, 400mg BID Compound 2, and RBV in treatment naïve subjects infected with GT1HCV.

Group 3. Peginterferon+ribavirin (P/RBV) non-responders were treatedwith a protease inhibitor (in combination with ritonavir), a polymeraseinhibitor, and ribavirin. The treatment was without interferon.

Subjects included 17 P/RBV non-responders between the ages of 18 and 65.Subjects were treated with Compound 1/r dosed in combination withCompound 2 and RBV for 12 weeks. Compound 1 (150 mg QD) was dosed with100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in P/RBVnon-responders infected with GT1 HCV. During the treatment, fourpatients had breakthroughs and discontinued the study before week 7.

The baseline characteristics of the patients are shown in the tablebelow.

TABLE 2 Group 1 Group 2 Group 3 Genotype (1a/1b) 17/2 11/3 16/1 IL28B:CC 10  5 0 CT 7 7 11  TT 2 2 5 Undetermined 0 0 1 Median baseline HCVRNA 6.4 [4.1-7.2] 6.9 [3.1-7.5] 6.9 [6.0-7.8] (log IU/mL)

Results from Group 1. Ten of the nineteen subjects had HCV RNA <25 IU/mLat 2 weeks. Another eight had undetectable levels of HCV RNA at 2 weeks.At week 3, one subject discontinued, four of the remaining 18 subjectshad HCV RNA levels of less than 25 IU/mL, and fourteen of the remaining18 subjects had undetectable levels of HCV RNA. At week 4, seventeen ofthe remaining 18 subjects had undetectable levels of HCV RNA; onesubject had HCV RNA<25 IU/mL. At week 5, all of the remaining 18subjects had undetectable levels of HCV RNA. At week 6, seventeen of theremaining 18 subjects had undetectable levels of HCV RNA, and onesubject had HCV RNA <25 IU/mL. At weeks 7, 8, 9, 10, 11 and 12, all ofthe remaining 18 subjects had undetectable levels of HCV RNA (onesubject was not tested at week 12). At post-treatment weeks 2, 4, 8, and12 all of the remaining 18 subjects (including the one who was nottested at week 12 during treatment) had undetectable levels of HCV RNA.At post-treatment week 24, seventeen of the remaining 18 subjects weretested, and all of the seventeen subjects tested had undetectable levelsof HCV RNA. At post-treatment week 24, all of the remaining 18 subjectswere tested and found no detectable levels of HCV RNA.

Results from Group 2. Of the thirteen subjects tested, six had HCV RNA<25 IU/mL at 2 weeks. Another six subjects had undetectable levels ofHCV RNA at 2 weeks. At week 3, two subjects had HCV RNA levels of lessthan 25 IU/mL, and ten subjects had undetectable levels of HCV RNA.Eleven of the thirteen subjects had undetectable levels of HCV RNA at 4weeks and two had HCV RNA <25 IU/mL. At weeks 5, 6, 7, 8, 9 and 10, allthirteen subjects that were tested had undetectable levels of HCV RNA.One subject had detectable levels of HCV RNA at week 11 (the remaining12 subjects had undetectable levels of HCV RNA at week 11), but HCV RNAlevels in that subject, as well as all other subjects, were undetectableat week 12. At post-treatment weeks 2, 4, 8 and 12, all thirteensubjects tested (including the one who had detectable levels of HCV RNAat week 11 during treatment) had undetectable levels of HCV RNA. Atpost-treatment weeks 24, twelve of the thirteen subjects were tested andfound no detectable levels of HCV RNA.

Results from Group 3. Seven of the seventeen subjects tested had HCV RNA<25 IU/mL at 2 weeks. Another seven subjects had undetectable levels ofHCV RNA at 2 weeks. Three subjects had detectable levels of HCV RNA at 2weeks. At week 3, three subjects had HCV RNA levels of less than 25IU/mL, twelve subjects had undetectable levels of HCV RNA, and twosubjects had detectable levels of HCV RNA. At week 4, two subjects hadHCV RNA levels of less than 25 IU/mL, thirteen subjects had undetectablelevels of HCV RNA, and two subjects had detectable levels of HCV RNA.Sixteen subjects were tested at 5 weeks; thirteen subjects hadundetectable levels of HCV RNA and three subjects had detectable levelsof HCV RNA. Fifteen subjects were tested at 6 weeks; twelve subjects hadundetectable levels of HCV RNA and three subjects had detectable levelsof HCV RNA. All thirteen subjects that were tested at 7 weeks hadundetectable levels of HCV RNA. Twelve of the thirteen subjects thatwere tested at 8 weeks had undetectable levels of HCV RNA; one subjecthad HCV RNA levels of less than 25 IU/mL. All ten subjects that weretested at 9 weeks had undetectable levels of HCV RNA. Twelve of thethirteen subjects that were tested at 9 weeks had undetectable levels ofHCV RNA; one subject had detectable levels of HCV RNA. Twelve of thethirteen subjects that were tested at 10 weeks had undetectable levelsof HCV RNA; one subject had detectable levels of HCV RNA. Eleven of thetwelve subjects that were tested at 11 weeks had undetectable levels ofHCV RNA; one subject had HCV RNA levels of less than 25 IU/mL. Ten ofthe twelve subjects that were tested at week-12 of the treatment hadundetectable levels of HCV RNA; one subject had HCV RNA levels of lessthan 25 IU/mL, and another subject had detectable levels of HCV RNA. Theone subject that had HCV RNA levels of less than 25 IU/mL at week-12 ofthe treatment had breakthrough at post-treatment week 2. Atpost-treatment weeks 2 and 4, ten subjects that had undetectable HCV RNAat week-12 of the treatment were tested: eight of the ten subjects hadundetectable levels of HCV RNA; and the remaining two subjects haddetectable HCV RNA (breakthrough). The eight subjects that hadundetectable HCV RNA at post-treatment weeks 2 and 4 were further testat post-treatment weeks 8 and 12 and found no detectable HCV RNA.

The seventeen non-responder subjects in Group 3 included 6 nullresponders and 11 partial responders. Three out of the six nullresponders, and five out of the eleven partial responders, achievedSVR12.

The study also showed that IL28B host genotype appeared not to havesignificantly impact on SVR12 in this study (including Groups 1, 2 and3).

EXAMPLE 2B

Use of 2-DAA Combination with Ribavirin to Treat Treatment-NaïveSubjects Infected with Genotype 1, 2 or 3

Genotype 1

Ten previously untreated subjects infected with HCV genotype 1 weretreated with a 2-DAA combination with ribavirin. The treatment wasinterferon-free and was designed to last 12 weeks. The 2-DAA combinationincluded Compound 1/r (200/100 mg QD) and Compound 4 (25 mg QD). Theweight based dosing of ribavirin ranged from 1000 to 1200 mg dividedtwice daily. At weeks 5, 6 and 7 of the treatment, nine of the tensubjects showed no detectable HCV RNA; and the remaining one subject hadHCV RNA levels of less than 25 IU/mL. At week 8 of the treatment, fiveof the nine subjects were tested and showed no detectable HCV RNA. Atweeks 9 and 10 of the treatment, four of the five subjects were furthertested and found no detectable HCV RNA. At week 11, two of the foursubjects were tested and found no detectable HCV RNA.

Additional testing showed that all of the initial ten subjects at weeks8, 9, 10 and 11 of the treatment had no detectable HCV RNA. At week 12,nine of the initial ten subjects showed undetectable HCV RNA, and onehad HCV RNA levels of less than 25 IU/mL. At post-treatment week 2, allof the ten subjects were tested (including the one with HCV RNA levelsof less than 25 IU/mL at week 12 of the treatment), and all ten subjectsshowed no detectable HCV RNA. At post-treatment weeks 4 and 8, all ofthe ten subjects were tested and found no detectable HCV RNA. Two of theten subjects were further tested at post-treatment week 12 and found nodetectable HCV RNA.

Genotype 2

Ten previously untreated subjects infected with HCV genotype 2 weretreated with the same regimen of this Example. At week 4 of thetreatment, all of the ten subjects were tested and showed no detectableHCV RNA. At weeks 5 and 6 of the treatment, all of the ten subjects weretested and found no detectable HCV RNA. At weeks 9-11 of the treatment,all of the ten subjects were further tested, and nine of them showed nodetectable HCV RNA, and one subject showed HCV RNA levels of less than25 IU/mL. At week 12 of the treatment, nine of the initial ten subjectswere tested, eight of the nine subjects found no detectable HCV RNA andone showed detectable HCV RNA.

The subject showing detectable HCV RNA at week 12 of the treatment wasconfirmed breakthrough at post-treatment week 2. Eight of the initialten subjects were also tested at post-treatment week 2 and found nodetectable HCV RNA; seven of the initial ten subjects were furthertested at post-treatment week 4 and found no detectable HCV RNA; threeof the initial ten subjects were further tested at post-treatment week 8and found no detectable HCV RNA; and one of the initial ten subject wasfurther tested at post-treatment week 12 and found no detectable HCVRNA.

Genotype 3

Similarly, ten previously untreated subjects infected with HCV genotype3 were treated with the same regimen of this Example. At week 5 of thetreatment, two subjects had viral rebound; seven of the remaining eightsubjects had no detectable HCV RNA; and one of the remaining eightsubjects had HCV RNA levels of less than 25 IU/mL. At week 12 of thetreatment, and among the eight non-breakthrough subjects, one subjectwas lost from the study, another showed detectable HCV RNA, and theremaining six found no detectable HCV RNA.

At post-treatment weeks 2, 4 and 8, two more subjects had breakthrough,and five subjects had no detectable HCV RNA.

One of the two subjects that had viral rebound at week 5 of thetreatment was treated with a combination of peginterferon and ribavirin(P/RBV) starting at week 12. After four weeks of the P/RBV treatment,the subject was tested and found no detectable HCV RNA.

EXAMPLE 2C Use of 2-DAA Combination with Ribavirin to TreatTreatment-Experienced Subjects Infected with Genotype 1

Six treatment-experienced subjects with HCV genotype 1 infection weretreated with a 2-DAA combination with ribavirin for 12 weeks. Thetreatment was interferon-free. The 2-DAA combination included Compound1/r (200/100 mg QD) and Compound 4 (25 mg QD). The weight based dosingof ribavirin ranged from 1000 to 1200 mg divided twice daily. Thesepatients had previously undergone a standard interferon/ribavirintherapy but were not responsive (interferon null responders).

At week 6 of the treatment, all six subjects showed no detectable HCVRNA. At week 8 of the treatment, all six subjects were tested and, amongthem, five showed no detectable HCV RNA and one had HCV RNA levels ofless than 25 IU/mL. At weeks 10 and 12 of the treatment, all sixsubjects were tested and found no detectable HCV RNA.

At post-treatment weeks 2 and 4, all six subjects were tested, one hadbreakthrough and the remaining five subjects found no detectable HCVRNA. At post-treatment week 8, the five non-breakthrough subjects werefurther tested and found no detectable HCV RNA.

EXAMPLE 2D Use of 3-DAA Combination with Ribavirin to TreatTreatment-Naïve or Treatment-Experienced Subjects Infected with Genotype1

Treatment-Naïve Patients

Six previously untreated subjects having HCV genotype 1 infection weretreated with a 3-DAA combination with ribavirin for 8 weeks. Thetreatment was interferon-free. The 3-DAA combination included Compound1/r (150/100 mg QD), Compound 2 (400 mg BID), and Compound 4 (25 mg QD).The weight based dosing of ribavirin ranged from 1000 to 1200 mg dividedtwice daily. At week 8 of the treatment, all six subjects had nodetectable HCV RNA. At post-treatment weeks 2, 4, 8 and 12, all sixsubjects had no detectable HCV RNA.

Nine previously untreated subjects having HCV genotype 1 infection weretreated with a 3-DAA combination with ribavirin for 12 weeks. Thetreatment was interferon-free. The 3-DAA combination included Compound1/r (150/100 mg QD or 100/100 mg QD), Compound 2 (400 mg BID), andCompound 4 (25 mg QD). The weight based dosing of ribavirin ranged from1000 to 1200 mg divided twice daily. At week 8 of the treatment, allnine subjects had no detectable HCV RNA. At week of the treatment, allnine subjects were tested and found no detectable HCV RNA. Atpost-treatment weeks 2, 4, 8 and 12, all of the nine subjects werefurther tested and showed no detectable HCV RNA.

Treatment-Experienced Patients

Ten treatment-experienced subjects with HCV genotype 1 infection weretreated with a 3-DAA combination with ribavirin: four subjects weretreated for 12-week, one subject was treated for 16-week treatment, andthe remaining five subjects were treated for 24-week treatment. Thetreatment was interferon-free. The 3-DAA combination included Compound1/r (150/100 mg QD or 100/100 mg QD), Compound 2 (400 mg BID), andCompound 4 (25 mg QD). The weight based dosing of ribavirin ranged from1000 to 1200 mg divided twice daily. These patients had previouslyundergone a standard interferon/ribavirin therapy but were notresponsive (interferon null responders).

At weeks 6, 8, 10 and 12 of the treatment, all ten subjects showed nodetectable HCV RNA.

At post-treatment weeks 2, 4 and 8, all of the four subjects in the12-week treatment regimen found no detectable HCV RNA; and two of thefour subjects were further tested at post-treatment week 12 and found nodetectable HCV RNA. At post-treatment weeks 2, 4 and 8, the one subjectin the 16-week treatment regimen found no detectable HCV RNA. One of thefive subjects in the 24-week treatment regimen were tested atpost-treatment weeks 2 and 4 and found no detectable HCV RNA.

EXAMPLE 3 Synergistic Concentrations of Compound 1 and Compound 2 inGenotype 1b HCV Replicon Assay

Examples 3-5 are for illustration and do not limit the scope of thisdisclosure in any way. Not to be bound by any theory, the unexpectedsynergistic effects from combining different classes of HCV inhibitors(e.g., a combination of a protease inhibitor (such as Compound 1) and apolymerase inhibitor (such as Compound 2), or a combination of aprotease inhibitor (such as Compound 1) and a NS5A inhibitor (such ascompound 4)) may contribute to the effectiveness of the short-duration,interferon-free therapies of the present technology.

Materials:

A replicon cell line was derived from the human hepatoma cell line Huh7.It was derived from HCV genotype 1b (Con1), and is a bicistronicsubgenomic replicon, essentially similar to those described in Science285(5424):110-3 (1999). The first cistron of the construct contains afirefly luciferase reporter and a neomycin phosphotransferase selectablemarker. Replicon cells were maintained in Dulbecco's Modified EagleMedia (DMEM) containing 100 IU/ml penicillin, 100 mg/ml streptomycin(Invitrogen), 200 mg/ml G418, an aminoglycoside antibiotic (Invitrogen)and 10% fetal bovine serum (FBS) at 37° C. and 5% CO₂.

Replicon Cell Culture:

Replicon cells were seeded at a density of 5000 cells per well of a96-well plate in 100 μl DMEM containing 5% FBS. The following day,Compounds 1 and 2 were diluted in dimethyl sulfoxide (DMSO) to generatea 200× stock in a series of 6 two-fold dilutions. The dilution serieswas then further diluted 100-fold in the medium containing 5% FBS.

Combination Studies:

Combination studies were performed to evaluate the interaction effectsof therapeutic agent 1 and therapeutic agent 2 in the replicon assaydescribed above. The purpose of these studies was to determine whetherthere are doses or concentrations of each compound where synergy orantagonism is demonstrated with the other compound. Three experimentswith three plates in each experiment were performed on three separatedays. Six concentrations of Compound 1 alone and six concentrations ofCompound 2 alone were assayed in each plate. In addition, 36combinations of concentrations of the two compounds were assayed foreach plate. The variable analyzed was the fraction of inhibition of theluciferase signal.

The dilutions of each compound were combined with the dilutions of theother compound in a checkerboard fashion. The concentrations tested werechosen to ensure that the EC₅₀ for each compound alone is in the middleof the serial dilution range. Medium with inhibitor(s) was added to thecell culture plates already containing 100 μl of DMEM with 5% FBS. Thecells were incubated in a tissue culture incubator at 37° C. and 5% CO₂for three days. The inhibitor effects of compounds on HCV replicationwere determined by measuring activity of a luciferase reporter geneusing a Luciferase Assay System kit (Promega) following themanufacturer's instructions. Passive Lysis buffer (30 μl, Promega) wasadded to each well, and the plates were incubated for 15 minutes withrocking to lyse the cells. Luciferin solution (100 μl, Promega) wasadded to each well and the luciferase activity was measured using aVictor II luminometer (Perkin-Elmer). To determine the EC₅₀, theluciferase inhibition data were analyzed using GraphPad Prism 4software. Three experiments were performed with three replicates perexperiment. The percent inhibition results were analyzed for synergy,additivity and antagonism according to the Pritchard and Shipman model(Antiviral Research 14:181-206 (1990)).

Combination Analysis:

Prichard and Shipman proposed a direct approach to solve this drug-druginteraction problem. The method was able to calculate theoreticaladditive effects directly from the individual dose-response curvesdetermined in the assay. The calculated theoretical additivity was thencompared to the experimental dose-response surface, and subsequentlysubtracted to reveal any areas of aberrant interaction. The followingequation was used to calculate the theoretical additive effects:Z=X+Y(1−X)=X+Y−XY,where Z is the total inhibition produced by the combination of drugs Xand Y, with X and Y representing the inhibition produced by drugs X andY alone respectively.

A difference between the actual observed fraction of inhibition and thepredicted value was calculated for each concentration combination foreach plate in each experiment to determine whether the observed combinedeffect was greater than the theoretical additive effect Z calculatedfrom the equation above. For each concentration combination, thereplicates (across all plates and experiments) were used to calculate amean difference between observed and predicted fraction of inhibition,its standard error and its two-sided 95% confidence interval.

Synergy or antagonism for a concentration combination was determinedbased on the following 2 rules: First, the 95% CI of the mean differencebetween observed and predicted fraction of inhibition at eachconcentration combination is calculated. If the lower bound of 95% CI islarger than zero, then the drug combination would be considered having asynergistic effect; if the upper bound of 95% CI is less than zero, thenthe drug combination would be considered having an antagonistic effect;otherwise, no significant antagonism or synergy at this concentrationcombination.

Second, the synergistic or antagonistic effect must have its relativemean difference, the absolute mean difference divided by itscorresponding observed mean inhibition, greater than 1%. By doing this,small differences of statistical significance caused by very smallvariance could be excluded.

Combination of Therapeutic Agent 1 and Therapeutic Agent 2:

The inhibitory effects on replicons produced by each drug alone or incombination with the other at concentrations up to ten-fold above theEC₅₀ were examined in the genotype 1b (Con1) replicon using acheckerboard titration pattern (two-fold serial dilutions) in a standardthree-day antiviral assay. The concentrations tested were chosen toensure that the EC₅₀ values of the compounds were in the middle of theserial dilution range. For Compound 1, concentrations ranged from 0.031nM to 1.0 nM. For Compound 2, concentrations ranged from 0.125 nM to 4.0nM. Synergy, additivity, and antagonism were evaluated using thePritchard and Shipman model.

Results:

The results of the assay analysis are illustrated in FIGS. 1 and 2 andTable 3. In the 3-D surface plot of FIG. 1, deviations from expectedinteractions between Compound 1 and Compound 2 are purely additive atconcentrations associated with a horizontal plane at 0%. Synergisticinteractions between Compound 1 and Compound 2 appear as a peak abovethe horizontal plane with a height corresponding to the percent abovecalculated additivity. Antagonistic interactions between Compound 1 andCompound 2 appear as a pit or trough below the horizontal plane with anegative value signifying the percent below the calculated additivity.Synergistic interactions appear as dark grey, additive interactionsappear white, and antagonistic interactions appear as speckled.

As illustrated in the 3-D surface plot of FIG. 1 and the contour plot ofFIG. 2, an additive or synergistic effect exists at most of theconcentrations for Compound 1 and Compound 2. In particular, there is aconcentration region showing synergy at most concentrations of Compound1 and at the lower to mid-range dose concentrations of Compound 2.

Table 3 below lists combinations of concentrations of Compound 1 andCompound 2 with statistically significant synergistic or antagonisticeffects based on the Prichard and Shipman model analysis. For eachcombination of concentrations, Table 3 includes the mean difference inthe observed and predicted fraction of inhibition, the standarddeviation or error of the mean difference, and the upper and lowerlimits of the 95% confidence interval.

According to Table 3, all of the combinations of Compound 1 and Compound2 listed in the table have statistically significant synergisticeffects.

The results presented in FIGS. 1 and 2 and Table 3 demonstrate that thecombination of therapeutic agent 1 and therapeutic agent 2 achievesadditivity or synergy at most of the concentration combinations of thetwo agents. Taken together, these in vitro replicon results suggest thattherapeutic agent 2 should produce a significant antiviral effect inpatients when administered in combination with therapeutic agent 1 inpatients infected with HCV.

TABLE 3 Mean difference in Compound Compound fraction of inhibition:Standard error Lower 95% Upper 95% 2, nM 1, nM Observed − Predicted ofmean difference confidence limit confidence limit .125 .12500 0.061760.023352 0.007912 0.11561 .125 .25000 0.05321 0.022199 0.002024 0.10440.125 .50000 0.01176 0.002680 0.005583 0.01794 .250 .25000c 0.066260.020630 0.018692 0.11384 .250 .50000 0.01061 0.002677 0.004438 0.01679.500 .06250 0.04373 0.014897 0.009375 0.07808 .500 .12500 0.104160.026757 0.042454 0.16586 .500 .25000 0.09327 0.019859 0.047471 0.13906.500 .50000 0.01422 0.003333 0.006535 0.02191 1.00 .06250 0.066960.020488 0.019715 0.11421 1.00 .12500 0.14103 0.021289 0.091939 0.190131.00 .25000 0.11027 0.016762 0.071617 0.14892 1.00 .50000 0.013650.002312 0.008315 0.01898 2.00 .06250 0.05974 0.007690 0.042004 0.077472.00 .12500 0.10032 0.011820 0.073066 0.12758 2.00 .25000 0.071170.009428 0.049428 0.09291 4.00 .03125 0.03235 0.003950 0.023236 0.041454.00 .06250 0.05141 0.004313 0.041470 0.06136 4.00 .12500 0.065720.004692 0.054901 0.07654 4.00 .25000 0.03452 0.004775 0.023509 0.04553

EXAMPLE 4 Synergistic Concentrations of Compound 1 and Compound 4 inGenotype 1b HCV Replicon Assay

Materials:

The replicon cell line was derived from the human hepatoma cell lineHuh7. It was derived from HCV genotype 1b (Con1), and is a bicistronicsubgenomic replicon, essentially similar to those described in Science285(5424):110-3 (1999). The first cistron of the construct contains afirefly luciferase reporter and a neomycin phosphotransferase selectablemarker. Replicon cells were maintained in Dulbecco's Modified EagleMedia (DMEM) containing 100 IU/ml penicillin, 100 mg/ml streptomycin(Invitrogen), 200 mg/ml G418 (Invitrogen) and 10% fetal bovine serum(FBS) at 37° C. and 5% CO₂.

Replicon Cell Culture:

Replicon cells were seeded at a density of 5000 cells per well of a96-well plate in 100 μl DMEM containing 5% FBS. The following day,compounds were diluted in dimethyl sulfoxide (DMSO) to generate a 200×stock in a series of 6 two-fold dilutions. The dilution series was thenfurther diluted 100-fold in the medium containing 5% FBS.

Combination Studies:

Combination studies were performed to evaluate the interaction effectsof therapeutic agent 1 and therapeutic agent 4 in the replicon assaydescribed above. The purpose of these studies was to determine doses orconcentrations of each compound where synergy or antagonism isdemonstrated with the other compound. Three experiments with threeplates in each experiment were performed on three separate days. Sixconcentrations of Compound 1 alone and six concentrations of Compound 2alone were assayed in each plate. In addition, 36 combinations ofconcentrations of the two compounds were assayed for each plate. Thevariable analyzed was the fraction of inhibition of the luciferasesignal.

The dilutions of each compound were combined with the dilutions of theother compound in a checkerboard fashion. The concentrations tested werechosen to ensure that the EC₅₀ for each compound alone is in the middleof the serial dilution range. Medium with inhibitor(s) was added to thecell culture plates already containing 100 μl of DMEM with 5% FBS. Thecells were incubated in a tissue culture incubator at 37° C. and 5% CO₂for three days. The inhibitor effects of compounds on HCV replicationwere determined by measuring activity of a luciferase reporter geneusing a Luciferase Assay System kit (Promega) following themanufacturer's instructions. Passive Lysis buffer (30 μl, Promega) wasadded to each well, and the plates were incubated for 15 minutes withrocking to lyse the cells. Luciferin solution (100 μl, Promega) wasadded to each well and the luciferase activity was measured using aVictor II luminometer (Perkin-Elmer). To determine the EC₅₀, theluciferase inhibition data were analyzed using GraphPad Prism 4software. Three experiments were performed with three replicates perexperiment. The percent inhibition results were analyzed for synergy,additivity and antagonism according to the Pritchard and Shipman model(Antiviral Research 14:181-206 (1990)).

Combination Analysis:

The Prichard and Shipman approach to calculating theoretical additiveeffects (described in Example 3) was used for the present example.

The difference between the actual observed fraction of inhibition andthe predicted value was calculated for each concentration combinationfor each plate in each experiment to determine whether the observedcombined effect was greater than the theoretical additive effect Zcalculated from the Prichard and Shipman equation. For eachconcentration combination, the replicates (across all plates andexperiments) were used to calculate a mean difference between observedand predicted fraction of inhibition, its standard error and itstwo-sided 95% confidence interval.

Synergy or antagonism for a concentration combination was determinedbased on the same rules set forth in Example 3.

Combination of Therapeutic Agent 1 and Therapeutic Agent 4:

The inhibitory effects in replicon produced by each drug alone or incombination with the other at concentrations up to ten-fold above theEC₅₀ were examined in the genotype 1b (Con1) replicon using acheckerboard titration pattern (two-fold serial dilutions) in thestandard three-day antiviral assay. The concentrations tested werechosen to ensure that the EC₅₀ values of the compounds were in themiddle of the serial dilution range. For compound 4, concentrationsranged from 0.0002 nM to 0.0063 nM, and for Compound 1, concentrationsranged from 0.023 nM to 0.75 nM. Synergy, additivity, and antagonismwere evaluated using the Pritchard and Shipman model.

Results:

The results of the assay analysis are illustrated in FIGS. 3 and 4 andTable 4. In the 3-D surface plot of FIG. 3, deviations from expectedinteractions between Compound 1 and compound 4 are purely additive atconcentrations associated with a horizontal plane at 0%. Synergisticinteractions between Compound 1 and compound 4 appear as a peak abovethe horizontal plane with a height corresponding to the percent abovecalculated additivity. Antagonistic interactions between Compound 1 andcompound 4 appear as a pit or trough below the horizontal plane with anegative value signifying the percent below the calculated additivity.Synergistic interactions appear as shades of dark grey, additiveinteractions appear white, and antagonistic interactions appear asspeckled.

As illustrated in the 3-D surface plot of FIG. 3 and the contour plot ofFIG. 4, an additive or synergistic effect exists at most of theconcentrations for Compound 1 and compound 4. In particular, there is aconcentration region showing synergy at the lower dose concentrations ofcompound 4 and mid-range dose concentrations of Compound 1.

Table 4 below lists combinations of concentrations of Compound 1 andcompound 4 with statistically significant synergistic or antagonisticeffects based on the Prichard and Shipman Model analysis. For eachcombination of concentrations, Table 4 includes the mean difference inthe observed and predicted fraction of inhibition, the standarddeviation or error of the mean difference, and the upper and lowerlimits of the 95% confidence interval.

According to Table 4, most of the combinations of Compound 1 andcompound 4 listed in the table have statistically significantsynergistic effects. A small amount of antagonism was observed at thelowest concentrations of Compound 1.

The results presented in FIGS. 3 and 4 and Table 4 demonstrate that thecombination of therapeutic agent 4 and therapeutic agent 1 achievesadditivity at most of the concentration combinations of the two agentsand achieves synergy at certain concentration combinations, inparticular, at low concentrations of therapeutic agent 4 and mid-rangeconcentrations of therapeutic agent 1. Taken together, these in vitroreplicon results suggest that therapeutic agent 4 should produce asignificant antiviral effect in patients when administered incombination with therapeutic agent 1 in patients infected with HCV.

TABLE 4 Mean difference in Compound Compound fraction of inhibition:Standard error Lower 95% Upper 95% 4, nM 1, nM Observed − Predicted ofmean difference confidence limit confidence limit 0.000197 0.3750000.09895 0.033975 0.02060 0.17729 0.000394 0.187500 0.16900 0.0389340.07922 0.25878 0.000394 0.375000 0.11401 0.027710 0.05011 0.177910.000788 0.187500 0.15349 0.038860 0.06388 0.24310 0.000788 0.3750000.09992 0.027266 0.03704 0.16279 0.001575 0.023438 −0.08326 0.027126−0.14582 −0.02071 0.001575 0.046875 −0.11894 0.026099 −0.17913 −0.058760.001575 0.187500 0.07958 0.020080 0.03328 0.12588 0.003150 0.023438−0.10156 0.018406 −0.14401 −0.05912 0.003150 0.046875 −0.08091 0.014615−0.11462 −0.04721

EXAMPLE 5 Reduction of HCV-Infected Cells with Combinations ofTherapeutic Agents 1, 2 and 4

In order to quantify the frequency of resistant replicon coloniesselected by therapeutic agent 1, therapeutic agent 2, therapeutic agent4, or various combinations of these agents, the stable subgenomicreplicon cell line derived from HCV genotype 1a (H77; Genbank accessionnumber AF011751) was utilized. The replicon construct was bicistronicand the cell line was generated by introducing the constructs into celllines derived from the human hepatoma cell line Huh-7. The replicon alsohas a firefly luciferase reporter and a neomycin phosphotransferase(Neo) selectable marker. The two coding regions, separated by the FMDV2a protease, comprise the first cistron of the bicistronic repliconconstruct, with the second cistron containing the HCV NS3-NS5B codingregion with addition of adaptive mutations E1202G, K1691R, K2040R andS2204I. This HCV replicon cell line was maintained in Dulbecco'smodified Eagles medium (DMEM; Invitrogen) containing 10% (v/v) fetalbovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 200μg/ml G418 (all from Invitrogen). 1a-H77 replicon cells (105-106) wereplated in 150 mm cell culture plates and grown in the presence of G418(400 μg/ml) and Compound 1, Compound 2, and/or compound 4 atconcentrations that were either 10-fold (10×) or 100-fold (100×) abovethe EC50 value for the HCV genotype 1a replicon cell line. The EC50values for Compound 1, Compound 2, and compound 4 used for thisexperiment were 0.9, 7.7, and 0.01 nM, respectively. After three weeksof treatment, the majority of replicon cells were cleared of repliconRNA and, therefore, were unable to survive in the G418-containing mediumsince the replicon RNA included the neo marker conferring G418resistance. The cells containing resistant replicon variants survivedand formed colonies, and these colonies were stained with 1% crystalviolet in 10% Protocol SafeFix II reagent (Fisher Scientific), andcounted. As shown in FIG. 5A, the combination of compound 4 plus eitherCompound 1 or Compound 2 at either 10-fold or 100-fold above theirrespective EC50 value resulted in significantly fewer colonies thaneither Compound 1, Compound 2, or compound 4 alone at 10-fold or100-fold above their respective EC50 value.

FIG. 5B illustrates the percentage of colonies surviving two vs. threeDAA combinations. In colony survival assays, 1a-H77 replicon cells weregrown in the presence of a DAA combination and G418 for approximatelythree weeks, after which time the cells containing resistant repliconvariants had formed colonies. The cells were stained with crystal violetand counted. “Triple Combination” is either a combination of Compounds1, 2 and 4 at concentrations of 5-fold (5×) over their respective EC50values, or a combination of Compounds 1, 2 and 4 at concentrations of10-fold (10×) over their respective EC50 values.

FIGS. 5C and 5D show the effect of a combination of Compounds 1 and 4 inlong-term HCV RNA reduction assays in genotype 1 replicon cell lines. Inlong-term replicon RNA reduction assays, 106 replicon cells were platedin the absence of G418. The inhibitors at concentrations of either10-fold (10×) or 100-fold (100×) over their respective EC₅₀ values wereadded, and the cells were grown to approximately 95% confluence (4days). At each passage, 106 cells were removed and frozen, and anadditional 106 cells were passed into another flask with fresh media andinhibitors. RNA was extracted from 106 cells and HCV RNA was measured ina Real-Time RT-PCR assay. FIGS. 5C and 5D show that in both 1a and 1breplicon cells, the combination of Compounds 1 and 4, each at 10-foldover EC₅₀, is more effective at clearing cells of replicon than 100-foldover EC₅₀ of either inhibitor alone.

Predominant resistant variants selected by Compound 1, 2, or 4 ingenotype 1 replicons were also determined. For Compound 1, thepredominant resistance variants in 1a-H77 replicons include R155K, D168Aand D168V with fold resistance of 26, 48 and 128, respectively; and thepredominant resistance variants in 1b-Con1 replicons include R155K,A156T and D168V with fold resistance of 48, 9 and 190, respectively. ForCompound 2, the predominant resistance variants in 1a-H77 repliconsinclude C316Y, M414T, Y448C and S556G with fold resistance of 1600, 36,980 and 15, respectively; and the predominant resistance variants in1b-Con1 replicons include C316Y, M414T and D559G with fold resistance of1400, 26 and 100, respectively. For Compound 4, the predominantresistance variants in 1a-H77 replicons include M28T, M28V, Q30R, Y93Cand Y93H with fold resistance of 9000, 60, 800, 1700 and 41000,respectively; and the predominant resistance variants in 1b-Con1replicons include Y93H with fold resistance of 55. These experimentsalso showed that in genotype 1a, a number of variants selected byCompounds 2 or 4 conferred higher levels of resistance than thoseselected by Compound 1, and that in genotype 1b, one variant (C316Y)selected by Compound 2 conferred a higher level of resistance than thoseselected by either Compound 1 or Compound 4.

The above examples show that the combination of two different classes ofDAAs (e.g., a combination of a HCV protease inhibitor and a HCVpolymerase inhibitor, or a combination of a HCV protease inhibitor and aHCV NSSA inhibitor, or a combination of a HCV polymerase inhibitor and aHCV NSSA inhibitor) can lead to an improved resistance barrier inpatients relative to a single DAA alone, while the combination of threedifferent classes of DAAs (e.g., a combination of a HCV proteaseinhibitor, a HCV polymerase inhibitor, and a HCV NS5A inhibitor) canlead to even more significant barrier to resistance. Improvement in thebarrier to resistance achieved through co-administration of multipleDAAs of different classes or with different mechanism of action isexpected to correlate with enhanced efficacy in patients.

EXAMPLE 6 Clinical Modeling for Interferon-Free DAA CombinationTherapies

This example describes a novel clinical model for evaluating optimaldoses and durations of interferon-free HCV therapies using combinationsof different DAAs. This model reasonably predicted the effectiveness ofnumerous DAA combinations in interferon-free, short-duration therapies.

A mechanistic model was used to model the relationship between DAAexposures and antiviral efficacy in HCV-infected subjects. This modelwas used to conduct clinical trial simulations of clinical outcomesfollowing administration of various DAA combination regimens (e.g.,specific DAA combinations and different doses of DAAs) and durations oftherapy.

Numerous DAAs have been extensively documented to select mutantsfollowing short duration of monotherapy (e.g., less than 1 week). Theviral dynamic model of this Example included single and double mutants.Specifically, the model included 2 single mutants and one double mutantfor each of the 2-DAA combination regimens. Thus, a 2-DAA combinationregimen (e.g., a combination of a protease inhibitor and a NS5Ainhibitor) included 2 single mutants and one double mutant. A 3-DAAcombination (e.g., a combination of a protease inhibitor, a polymeraseinhibitor and a NS5A inhibitor, such as a combination of a proteaseinhibitor, a non-nucleoside polymerase inhibitor (NNPI) and a NS5Ainhibitor) included 3 single and 2 double mutants.

The model has 3 components: hepatocytes (uninfected or target cell),infected cell and viral dynamics. The differential equations describingthe dynamics of the 3 components are as follows:

(1) Hepatocytes (Uninfected or Target Cell) DynamicsdT/dt=s−de*T−(1−η)*β*T*(VLWT+VLPoly+VLProt+VLNS5A+VLNS5AProt+VLPolyProt)

(2) Infected Cell Dynamics

(a) Infected with Wild type Virusd IWT/dt=(1−η)*β*T*VLWT−δ*IWT

(b) Infected with Polymerase Mutant Virusd IPoly/dt=(1−η)*β*T*VLPoly−δ*IPoly

(c) Infected with Protease Mutant Virusd IProt/dt=(1−η)*β*T*VLProt−δ*IProt

(d) Infected with NS5A Mutant Virusd INS5A/dt=(1−η)*β*T*VLNS5A−δ*INS5A

(e) Infected with Protease-NS5A Double Mutant Virusd INS5AProt/dt=(1−η)*β*T*VLNS5AProt−δ*INS5AProt

(f) Infected with Protease-Polymerase Double Mutant Virusd IPolyProt/dt=(1−η)*β*T*VLPolyProt−δ*IPolyProt

(3) Viral Dynamics

(a) Wild Type VirusdVLWT/dt=(1−3*μ)*ρ*(1−Eff1)*IWT+μ*(ρ*(1−Eff2)*Fit1*IPoly+ρ*(1−Eff3)*Fit2*IProt+ρ*(1−Eff4)*Fit3*INS5A)−c*VLWT

(b) Polymerase Mutant VirusdVLPoly/dt=(1−μ−φ)*ρ*(1−Eff2)*Fit1*IPoly+μ*ρ*(1−Eff1)*IWT+φ*ρ*(1−Eff5)*Fit4*IPoly−Prot−c*VLPoly

(c) Protease Mutant VirusdVLProt/dt=(1−μ−2*φ)*ρ*(1−Eff3)*Fit2*IProt+μ*ρ*(1−Eff3)*IWT+φ*(ρ*(1−Eff5)*Fit4*IPolyProt+ρ*(1−Eff6)*Fit5*INS5AProt)−c*VLProt

(d) NS5A Mutant VirusdVLNS5A/dt=(1−μ−φ)*ρ*(1−Eff4)*Fit3*INS5A+μ*ρ*(1−Eff1)*IWT+φ*ρ*(1−Eff6)*Fit5*INS5AProt−c*VLNS5A

(e) NS5A and Protease Double Mutant VirusdVLNS5AProt/dt=(1−2*φ)*ρ*(1−Eff6)*Fit5*INS5AProt+φ*(ρ*(1−Eff4)*Fit3*INS5A+ρ*(1−Eff3)*Fit2*IProt)−c*VLNS5AProt

(f) Poly and Protease Mutant Double Mutant VirusdVLPolyProt/dt=(1−2*φ)*ρ*(1−Eff5)*Fit4*IPolyProt+φ*(ρ*(1−Eff2)*Fit1*IPoly+ρ*(1−Eff3)*Fit2*IProt)−c*VLPolyProt

The parameters used in the above equations are described in Table 5.

TABLE 5 Viral Dynamic Parameters Parameter Description s zero-orderproduction of hepatocytes T number of Target or uninfected hepatocytesde first-order rate constant for the death of hepatocytes βrate-constant for the infection of hepatocytes by virus δ first-orderrate constant for the death of infected hepatocytes η fractionalreduction of the rate-constant for the infec- tion of hepatocytes byvirus μ probability of the formation of single mutants and mutation backto Wild-Type φ probability of the formation of double mutants andmutation back to single mutant ρ production rate of the Wild-Type virusc clearance rate of the virus Eff1, Eff2, inhibition of production ofWild Type, polymerase, Eff3, Eff4 protease, and NS5A mutant,respectively Eff5, Eff6 inhibition of production of polymerase-proteaseand NS5A-protease double mutant, respectively Fit1, Fit2, fitness ofpolymerase, protease and NS5A mutant Fit3 relative to wild type virus,respectively Fit4, Fit5 fitness of polymerase-protease and NS5A-proteasedouble mutant relative to wild type virus, respectively IWT, IPoly,number of cells infected with wild type, polymerase, Iprot, INS5Aprotease and NS5A mutants, respectively IPoly-Prot, number of cellsinfected with polymerase-protease and INS5A-Prot NS5A-protease doublemutant, respectively VLWT, VLPoly, viral load for wild type virus,polymerase, protease VLProt, VLNS5A and NS5A mutant virus, respectivelyVLPoly-Prot, viral load for polymerase-protease and NS5A-proteaseVLNS5A-Prot double mutant, respectively

As shown in the differential equations for viral dynamics, the effect ofDAA is included as an inhibition of viral load production. For example,the effect of DAA(s) on production of wild type virus is given as(1-Eff1)*ρ where Eff1 is the fraction of viral production that isinhibited. In the absence of drug Eff1=0 and in the presence of drugEff1 takes a value between 0 and 1. Eff1 is described using an Emaxmodel:Eff1=Emax*Conc/(EC₅₀+Conc)where Emax represents maximum inhibition, Conc is the plasma DAAconcentration and EC₅₀ is the concentration that inhibits viral loadproduction by 50%. As the fold-change in EC₅₀ for the mutants comparedto wild type virus was based on values obtained from in vitro repliconstudies, EC₅₀ was estimated only for wild type virus.

For DAA combinations, the effect was assumed to be multiplicative andincorporated as follows:(1−Eff1)=(1−Eff_(DAA1))*(1−Eff_(DAA2))*(1−Eff_(DAA3))

The effect of ribavirin (RBV) was added on infection rate (3 as an Emaxmodel. In presence of ribavirin, the infection rate decreases by afactor (1-1)) whereη=Conc_(RVB)/(EC_(50-RBV)+Conc_(RVB))

The model does not include a double mutant to the polymerase+NS5Ainhibitors. In a 3-DAA regimens, a polymerase+NS5A double mutant isoften wild type for the protease inhibitor. Hence, this double mutant isnot expected to significantly affect clinical outcomes for a 3-DAAregimen simulation. On the other hand, the model can be readily adaptedto simulate a 2-DAA regimen containing a polymerase inhibitor and a NS5Ainhibitor by treating the polymerase inhibitor (e.g., PSI-7977) as aprotease inhibitor in the model.

The lowest available limit of detection (LOD) of viral load assays is 10IU/mL. Assuming 3 virion particles per IU, this constitutes about 0.5million viruses in the body at LOD. Hence, subjects have to be treatedfor significant period of time after their viral load falls below theLOD to achieve cure. This duration depends on the potency of thecompounds and the individual response to therapy.

In order to predict the duration required for cure, a “threshold”concept was used. For simulations, an HCV-infected subject was assumedto achieve SVR when viral load reaches less than 1 virion in the totalplasma and extracellular fluid volume (about 15000 mL), i.e., viral loadmeasurement of <1 copy/15000 mL or <0.33 IU/15000 mL. This translates toabout 5 log IU/mL. Cf Snoeck E et al., CLIN PHARMACOL THER. 87(6):706-13(2010), wherein based on data from patients treated with peg-IFN andribavirin, subjects were estimated to achieve SVR when the predictednumber of infected cells fell below 1. While such low viral loads cannotbe measured experimentally, they can be simulated using the viraldynamic model.

The model can be used to predict SVR for any combination of DAAs, withor without interferon, and with or without ribavirin.

As non-limiting examples, various interferon-free treatment regimensusing different combinations of Compound 1, Compound 2 and/or Compound4, with or without ribavirin, were evaluated using the model of thisExample. The following approach was used to include mutants in themodel:

-   -   a. One single mutant per DAA    -   b. One double mutant per DAA combination

For a combination of two DAAs, e.g., a combination of Compound 1 andCompound 2, the model included one mutant resistant to Compound 1, onemutant resistant to Compound 2, and one double mutant resistant to bothCompound 1 and Compound 2. Compound 1 is coadministered or co-formulatedwith ritonavir (or another pharmacokinetics enhancer) to improve itsdrug exposure.

A double mutant to Compound 2 and Compound 4 was not included in themodeling. In the 3-DAA regimens, a Compound 2/Compound 4 double mutantis likely wild type for Compound 1 due to the high potency and resistantprofile of Compound 1. Hence, the Compound 2/Compound 4 double mutant isnot expected to affect clinical outcomes for treatments containingCompound 1.

Single mutants included in the model were based on mutants observed forthe individual DAAs in the Phase 1b and 2a studies (e.g., clinicalstudies M10-351, M12-116, and M11-602). For double mutants withresistance to 2 DAA classes, the sensitivity (EC₅₀) of double mutants todrug was assumed to be a combination of the 2 single mutants. Thus, forCompound 1 and Compound 2, the single mutants were D168V and M414T,respectively, and the double mutant was D168V-M414T. In this scenario,the D168V mutant would be less sensitive to Compound 1 but would be assensitive to Compound 2 as wild type virus. Similarly, the M414T mutantwould be less sensitive to Compound 2 but would be as sensitive toCompound 1 as wild type virus. The double mutant D168V-M414T would beless sensitive to both Compound 1 and Compound 2.

The fold change in EC₅₀ for the mutants compared to wild type virus wasbased on values obtained from in vitro replicon studies. Sincemonotherapy data for Compound 4 indicated a variety of mutants withdifferent EC₅₀s, a value of 1000× fold change in EC₅₀ was used forCompound 4 for modeling and simulations.

Baseline prevalence of the mutants was estimated during model fitting,while the mutation rate was based on the literature values. Bothbaseline prevalence and mutation rate determined mutant fitness.

Pharmacokinetic data and viral load data from 140 treatment-naïveHCV-infected subjects were used to construct the model. For modeling,number of target cells at baseline, number of infected cells atbaseline, death rate of target cells and mutation rates were based onliterature values. See, e.g., Snoeck et al. supra; Rong et al. SCITRANSL MED. 2(30):30ra32 (2000); Neal and Pravin, ACOP 2009(http://2009.go-acop.org/sites/all/assets/webform/Lauren-Neal_ACoP_(—)2009.pdf);Neumann et al. SCIENCE 282(5386):103-7 (1998); Shudo et al. ANTIVIRTHER. 13(7):919-26 (2008); and Dahari et al. J THEOR BIOL. 247(2):371-81(2007). The production rate of virus and infection rate of virus werederived from other parameters in the model. All other parameters wereestimated. Exposure-antiviral response modeling was performed usingNONMEM 7.2.

Clinical trial simulations were performed using Trial Simulator version2.2.1. Fifty subjects and 50 replicates were simulated for eachtreatment. A subject drop out rate from the study due to any reason wasassumed to be 8% over 24 weeks based on available literature on trialsin subjects with HCV. All simulations were conducted assuming 100%compliance. Covariates included in the simulations were genotype 1a/1bstatus. Clinical outcomes simulated included: (1) percentage of subjectsbelow limit of detection (LOD) of 10 IU/mL and (2) percentage ofsubjects achieving SVR.

Clinical trial simulations were conducted to determine optimal dose andduration for SVR. Over 80 scenarios were simulated to predict thepercentage of subjects with SVR following administration of various 2-and 3-DAA combinations (e.g., Compound 1+Compound 2, or Compound1+Compound 4, or Compound 1+Compound 2+Compound 4), without RBV, at arange of doses for each DAA (e.g., Compound 1/ritonavir at 250/100,150/100 or 100/100 mg QD, Compound 4 at 5, 25 or 100 mg QD, and Compound2 at 400 or 800 mg BID) and across a range of treatment durations (e.g.,2. 4, 6, 8, 10, 12, 16, and 24 weeks).

Optimal dose and duration were predicted based on percentage of subjectswith viral load of less than −5 log IU/mL threshold for SVR. Selectedand relevant results of simulation for the 2- and 3-DAA combinations ofCompounds 1, 2 and/or 4 are shown in FIGS. 6A, 6B and 6C for twodifferent doses of Compound 1. FIG. 6A shows the predicted median SVRpercentage (“% SVR”) and 90% confidence interval (the vertical bar atthe top of each SVR percentage column) for different treatment durationsusing a combination of Compound 1 and Compound 2; FIG. 6B shows thepredicted median and 90% confidence interval for different treatmentdurations using a combination of Compound 1 and Compound 4; and FIG. 6Cshows the predicted median and 90% confidence interval for differenttreatment durations using a combination of Compound 1, Compound 2 andCompound 4. In each simulation, RBV was included, and Compound 1 wasused with 100 mg ritonavir, and the subjects are HCV genotype 1,treatment-naïve patients. SVR24 is lower than SVR12 in some cases due todrop out; longer durations are not necessarily predicted to improve SVRbut could result in more dropouts resulting in lower SVR.

The model predicted that with 8-12 weeks of dosing at least 80 to 90%subjects can achieve SVR with 2 and 3 DAA combinations. The model alsopredicted that durations shorter than 8 weeks can cure a significantnumber of subjects. A 2-DAA regimen was predicted to cure over 40% ofthe subjects and a 3-DAA regimen was predicted to cure about 60% of thesubjects with only 6 weeks of dosing. Dosing for durations of over 12weeks was not expected to increase the percentage of subjects with SVRsignificantly. Addition of the 3^(rd) DAA was predicted to shortentreatment duration by 2 to 4 weeks as optimal durations for the 3-DAAcombination of Compound 1, Compound 2 and Compound 4 were predicted tobe 8-10 weeks.

FIGS. 6A, 6B and 6C illustrate the predictions for DAA combinationswithout ribavirin. The model also predicts similar or comparable SVRpercentages for these DAA combinations when used with ribavirin. Inaddition, the effect of interferon (e.g., pegylated interferon) can alsobe added by incorporating interferon similar to a DAA but without anyresistant mutants.

One of the advantages that the model provides is that it allowsexamination of various viral parameters and its effect on dose, durationand SVR. For example while experimentally determining the effect ofmutants parameters is very difficult if not impossible, they can beexamined using the model. Thus SVR in patient population that havedifferent mutants can be predicted with the model.

The model was used to simulate the treatment described in Example 1which included 150/100 mg Compound 1/ritonavir QD+400 mg Compound 3QD+weight-based amounts of RBV BID for 12 weeks, and the percentage ofsubjects with HCV RNA less than LOD at 2, 4, 8, 10, and 12 weeks wassummarized in FIG. 7. The mean predicted versus observed percentage ofsubjects with below LOD (“% LOD”) at respective weeks are shown FIG. 7.95% confidence intervals for the predicted data (the vertical bar at thetop of each respective predicted LOD percentage column) were alsoindicated. As shown in FIG. 7, the model reasonably predicted theclinical outcome of % LOD.

The model was also used to simulate the treatment described in Example2A. The mean predicted versus observed percentage SVR (“% SVR”) after12-week treatment are shown FIG. 8. 95% confidence intervals for thepredicted data (the vertical bar at the top of each respective predictedSVR percentage column) were also indicated. As shown in FIG. 8, thepredicted SVR percentages aligned well with the observed SVRpercentages. Simulations also predict that the same treatment regimen asdescribed in Example 2A but without ribavirin has similar or comparableLOD percentages for different treatment durations.

The exposure response viral dynamic model of this Example provided aquantitative method to reasonably predict SVR for various combination ofantiviral compounds. Based on the exposure-antiviral response modelingand clinical trial simulations, it demonstrated that (1) addition of a3^(rd) DAA to a 2-DAA combination can reduce optimal duration oftreatment and/or increase SVR; (2) 8-12 weeks of dosing is the optimalduration of therapy for 2 and 3 DAA combinations of Compound 1/r,Compound 2 and Compound 4; and (3) durations shorter than 8 weeks ofinterferon-free treatment have been predicted to cure a significantpercent of the subjects.

EXAMPLE 7 Clinical Modeling for Interferon-Free DAA CombinationTherapies Containing BMS-790052 and BMS-650032

The model described above was also used to predict the SVR percentage ofinterferon-free treatment regimens containing BMS-790052 and BMS-650032without ribavirin, based on existing published clinical data includingtwo Phase 1 and one Phase 2 study of BMS-790052 and one Phase 1 and onePhase 2a study of BMS-650032. FIG. 9 shows the predicted median SVRpercentage and 90% SVR confidence interval for different treatmentdurations of a 2-DAA regimen containing BMS-790052 (60 mg QD) andBMS-650032 (600 BID) in genotype 1 naïve subjects. The combination ofBMS-790052 (60 mg QD) plus BMS-650032 (600 mg BID) in genotype 1subjects was predicted to achieve improved SVR for durations of 12 weeksor greater with predicted SVR rates of about 70% for 10 weeks of dosing.Similar regimens but containing ribavirin, or regimens with similardosings of BMS-790052 and BMS-650032 with or without ribavirin, areexpected to achieve similar SVR rates.

EXAMPLE 8 Clinical Modeling for Interferon-Free Therapies ContainingPSI-7977

Likewise, a 3-DAA regimen without interferon and ribavirin was modeledfor genotype 1 patients based on existing clinical data. The 3-DAAregimen contains 200/100 mg QD Compound 1/r, 50 mg QD Compound 4, and400 mg QD PSI-7977. FIG. 10 depicts the predicted median SVR rates fordifferent treatment durations of this 3-DAA combination. This 3-DAAcombination was predicted to have over 60% SVR in 6 weeks and over 80%SVR at duration of 8-week, 10-week, 12-week or longer treatment. Similarregimens but containing ribavirin, or regimens with similar dosings ofCompound 1/r, Compound 4 and PSI-7977 with or without ribavirin, areexpected to achieve similar SVR rates.

The model can also be used to predict SVR for regimens containing singleDAA or single DAA with ribavirin. For example, the model predictions forPSI-7977+ribavirin for various durations for treating HCV genotype 1treatment-naïve patients were obtained. FIG. 11 depicts the predictedmedian and 90% confidence interval of SVR percentage for differenttreatment durations of such a regimen containing PSI-7977 (as the soleDAA; 400 mg QD) and ribavirin (600 mg BID). The 90% confidence intervalfor the predicted SVR (the vertical bar at the top of each respectivepredicted SVR percentage column) is also indicated in FIG. 11. Theprediction was based on the already published clinical data forPSI-7977. SVR rate for PSI-7977+ribavirin was predicted to be around75-90% following 12 weeks of dosing, and about 55-75% following 8 weeksdosing, in genotype 1 subjects. Similar SVR percentages for genotype 1treatment-naïve patients are expected for similar regimens containingsimilar PSI-7977 QD dosing (e.g., 200-600 mg QD) and weight-basedamounts of ribavirin (e.g., 1000 to 1200 mg divided twice daily).

Data from two Phase 1 and one Phase 2 study of Daclatasvir (BMS-790052)and one Phase 1 and one Phase 2 study of PSI-7977 were used forestimating the pharmacokinetic and viral dynamic model parameters.Predictions for a 2-DAA combination with Daclatasvir (BMS-790052) andPSI-7977 in genotype 1 naïve patients are shown in FIG. 12. The modelpredicted that following 10-12 weeks of dosing with the combination ofDaclatasvir and PSI-7977 without ribavirin, at least 90% of HCV genotype1 naïve patients can achieve SVR. Similar or better SVR rates arepredicted if ribavirin is included in the regimens.

Similarly, data from one Phase 1a study of TMC-435 and one Phase 1 andone Phase 2 study of PSI-7977 were used for estimating thepharmacokinetic and viral dynamic model parameters. Predictions for a2-DAA combination with the TMC-435 and PSI-7977 in genotype 1 naïvepatients are shown in FIG. 13. The model predicts that following 10-12weeks of dosing with the combination of TMC-435 and PSI-7977 withoutribavirin, at least 90% of HCV patients can achieve SVR. Similar orbetter SVR rates are predicted if ribavirin is included in the regimens.

EXAMPLE 9 Clinical Modeling for Interferon-Free DAA CombinationTherapies Containing Danoprevir and Mercitabine

In addition, data from one Phase 1 and one Phase 2 study of Danoprevirand Mercitabine were used for estimating the pharmacokinetic and viraldynamic model parameters. Ritonavir was co-administered with danoprevirto improve the pharmacokinetics of Danoprevir. Predictions for a 2-DAAcombination with Danoprevir and Mercitabine in genotype 1 naïve patientsare shown in FIG. 14. The model predicts that following 16 weeks ofdosing with the combination of Danoprevir and Mercitabine withoutribavirin, at least 90% of HCV patients can achieve SVR. Similar orbetter SVR rates are predicted if ribavirin is included in the regimens

EXAMPLE 10 Clinical Modeling for Interferon-Free DAA CombinationTherapies Containing Tegobuvir (GS-9190), GS-9451 and GS-5885

Data from Phase 1 and Phase 2 studies of GS-9190 (tegobuvir), GS-9451and GS-5885 were used for estimating the pharmacokinetic and viraldynamic model parameters. Predictions for the combination with GS-9190(tegobuvir), GS-9451 and GS-5885 in genotype 1 naive patients are shownin FIG. 15. The model predicts that following 12 weeks of dosing withthe combination of GS-9190 (tegobuvir)+GS-9451+GS-5885+RBV, about 70% ofgenotype 1 naïve patients can achieve SVR and following 24 weeks oftreatment ≧80% of genotype 1 naïve patients can achieve SVR. Similar orbetter SVR rates are expected when ribavirin is included in the regimen.

EXAMPLE 11 Clinical Modeling for Interferon-free DAA CombinationTherapies Containing PSI-7977 (GS-7977)

Data from Phase 1 and Phase 2 studies of GS-9451 and GS-7977 (PSI-7977)were used for estimating the pharmacokinetic and viral dynamic modelparameters. Predictions for the combination with GS-9451 and GS-7977(PSI-7977) in genotype 1 naive patients are shown in FIG. 16.

Data from Phase 1 and Phase 2 studies of GS-5885 and GS-7977 (PSI-7977)were used for estimating the pharmacokinetic and viral dynamic modelparameters. Predictions for the combination with GS-5885 and GS-7977(PSI-7977) in genotype 1 naive patients are shown in FIG. 16.

Data from Phase 1 and Phase 2 studies of GS-9451, GS-5885 and GS-7977(PSI-7977) were used for estimating the pharmacokinetic and viraldynamic model parameters. Predictions for the combination with GS-9451,GS-5885 and GS-7977 (PSI-7977) in genotype 1 naive patients are shown inFIG. 16.

The model predicts that following 12 weeks of dosing with thecombination of GS-9451 and GS-7977 (PSI-7977), or the combination ofGS-5885 and GS-7977 (PSI-7977), or the combination of GS-9451, GS-5885and GS-7977 (PSI-7977), at least 90% of genotype 1 naïve patients canachieve SVR. Similar or better SVR rates are expected when ribavirin isincluded in these regimens.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

What is claimed is:
 1. A method of treatment for HCV, comprisingadministering at least two direct acting antiviral agents (DAAs) andribavirin to a patient infected with HCV genotype 1, wherein saidtreatment lasts for 8 or 12 weeks and does not include administration ofinterferon to said patient, wherein said at least two DAAs compriseCompound 1

 Compound 4

 and PSI-7977, and wherein Compound 1 is administered with ritonavir. 2.The method of claim 1, wherein said patient is a treatment-naïvepatient.